TAG HIV Basic Science, Vaccines, and Cure Project Blog

Defining Elite Controllers

Elite controller is a term applied to the rare group of HIV-positive individuals who maintain undetectable viral loads in the absence of any treatment. The precise criteria for defining elite controllers often varies from study to study, particularly when it comes to the duration of viral load control. A research group based in the UK has recently published two companion papers—a systematic review and a research study—that attempt to document the various definitions that have been used in the scientific literature and identify the most accurate using data from a large cohort of HIV-positive individuals.

The review appears in the journal AIDS and has been made open access. The authors, led by Deepti Gurdasani, evaluated a staggering 501 papers to assess the definitions employed for groups of HIV-positive individuals at both ends of the disease progression spectrum, including rapid progressors, slow progressors, long-term non-progressors and elite controllers. The findings show that definitions for each group can vary, but in many cases overlap. In some instances, however, small differences can lead to similar definitions capturing significantly different populations. The authors recommend using their work as a starting point to try and achieve broad consensus in the research community about the most appropriate definitions for each group, so that there is consistency from study to study.

For elite controllers, a total of 50 unique definitions were identified. Viral load thresholds varied from 40 to 500 copies, with 50 being the most common. Slightly less than half the definitions included a minimum duration of follow up, which ranged from six months to 16 years.

In the second paper, published by PLoS One, the researchers take 10 of the identified elite controller definitions and analyze their performance using data from 25,692 participants in the CASCADE cohort, which comprises HIV-positive individuals followed since seroconversion. For participants that fell under each different elite controller definition, a variety of outcomes were assessed including how long they continued to meet the definition, disease progression, viral load, CD4 T cell count and CD4 T cell slope.

The results confirmed the rarity of elite controllers, with most definitions capturing around 1% or less of participants. Table 4 in the paper shows how many individuals fell under each different definition, and, of those, how many progressed to a composite endpoint of AIDS, death, initiation of ART, or CD4 T cell count of less than 350 cells. Only four people met the strictest definition of HIV-positive for 10 years or more with all viral load measurements below 50 copies. The definitions with the lowest number of progression events included:

• HIV-positive for 6 months or more, with two or three consecutive viral load measurements below 75 copies.
• HIV-positive for 10 years or more, with 90% of viral load measurements below 400 copies.

While risk of progression was greatly reduced among all elite controllers compared to non-elite controllers, the researchers note that some progression events were documented among all definitions. Furthermore, there was strong evidence of CD4 T cell declines for five out of the 10 definitions during the period considered as elite control. Based on these findings they conclude that it is unlikely that most elite controllers will remain so indefinitely. This conclusion echoes other recent studies documenting that elite control is associated with elevated levels of immune activation, which can in some cases lead to CD4 T cell loss and progression to AIDS. Although it has been proposed that elite control might be considered a model for a functional cure of HIV infection, these findings reinforce that it does not necessarily represent complete protection from the development of disease. This also has implications for examples of post treatment control such as the VISCONTI cohort and the first Berlin patient (see yesterday’s post), since it is as yet uncertain if the duration of control will be lifelong or, as with some elite controllers, progression might ultimately occur.

AIDS. 2014 Jan 14;28(2):149-62. doi: 10.1097/QAD.0000000000000049.

A systematic review of definitions of extreme phenotypes of HIV control and progression. 

Gurdasani D, Iles L, Dillon DG, Young EH, Olson AD, Naranbhai V, Fidler S, Gkrania-Klotsas E, Post FA, Kellam P, Porter K, Sandhu MS.

Abstract

The study of individuals at opposite ends of the HIV clinical spectrum can provide invaluable insights into HIV biology. Heterogeneity in criteria used to define these individuals can introduce inconsistencies in results from research and make it difficult to identify biological mechanisms underlying these phenotypes. In this systematic review, we formally quantified the heterogeneity in definitions used for terms referring to extreme phenotypes in the literature, and identified common definitions and components used to describe these phenotypes. We assessed 714 definitions of HIV extreme phenotypes in 501 eligible studies published between 1 January 2000 and 15 March 2012, and identified substantial variation among these. This heterogeneity in definitions may represent important differences in biological endophenotypes and clinical progression profiles of individuals selected by these, suggesting the need for harmonized definitions. In this context, we were able to identify common components in existing definitions that may provide a framework for developing consensus definitions for these phenotypes in HIV infection.

PLoS One. 2014 Jan 28;9(1):e86719. doi: 10.1371/journal.pone.0086719. eCollection 2014.

An Evaluation of HIV Elite Controller Definitions within a Large Seroconverter Cohort Collaboration.

Olson AD1, Meyer L2, Prins M3, Thiebaut R4, Gurdasani D5, Guiguet M6, Chaix ML7, Amornkul P8, Babiker A1, Sandhu MS5, Porter K1; for C. A. S. C. A. D. E. Collaboration in EuroCoord. 

Abstract

BACKGROUND: Understanding the mechanisms underlying viral control is highly relevant to vaccine studies and elite control (EC) of HIV infection. Although numerous definitions of EC exist, it is not clear which, if any, best identify this rare phenotype.

METHODS: We assessed a number of EC definitions used in the literature using CASCADE data of 25,692 HIVseroconverters. We estimated proportions maintaining EC of total ART-naïve follow-up time, and disease progression, comparing to non-EC. We also examined HIV-RNA and CD4 values and CD4 slope during EC and beyond (while ART naïve).

RESULTS: Most definitions classify ∼1% as ECs with median HIV-RNA 43-903 copies/ml and median CD4>500 cells/mm(3). Beyond EC status, median HIV-RNA levels remained low, although often detectable, and CD4 values high but with strong evidence of decline for all definitions. Median % ART-naïve time as EC was ≥92% although overlap between definitions was low. EC definitions with consecutive HIV-RNA measurements <75 copies/ml with follow-up≥ six months, or with 90% of measurements <400 copies/ml over ≥10 year follow-up preformed best overall. Individuals thus defined were less likely to progress to endpoint (hazard ratios ranged from 12.5-19.0 for non-ECs compared to ECs).

CONCLUSIONS: ECs are rare, less likely to progress to clinical disease, but may eventually lose control. We suggest definitions requiring individuals to have consecutive undetectable HIV-RNA measurements for ≥ six months or otherwise with >90% of measurements <400 copies/ml over ≥10 years be used to define this phenotype.

Update Published on the First Berlin Patient

In the late 1990s, a single case report about an individual displaying control of HIV viral load for nearly two years after interrupting antiretroviral therapy (ART) drew a huge amount of publicity, including a lengthy story in the New York Times magazine by Mark Schoofs in June of 1998. The case report was ultimately published in the New England Journal of Medicine on May 27, 1999. The man was dubbed “the Berlin patient” long before the moniker was also applied to Timothy Brown, the only adult considered cured of HIV infection. This first Berlin patient was under the care of Dr. Heiko Jessen, and he was treated with the unusual combination of ddI (Videx), indinavir (Crixivan) and the cancer drug hydroxyurea (which at the time was sometimes used both to potentiate ddI and for possible immune-modulating activity). Treatment was started during acute infection and subsequently interrupted twice for short periods before being completely discontinued. During the second interruption and after discontinuation, HIV viral load levels remained undetectable based on the assay in use, which had a cut-off of 500 copies/ml. The individual was reported to have strong HIV-specific CD4 T cell and CD8 T cell responses, suggesting cellular immunity might be responsible for the salutary outcome.

The case was influential in generating the hypothesis that treatment of acute infection followed by structured treatment interruptions might boost HIV-specific CD4 T cell and CD8 T cell responses and lead to post treatment control of HIV replication. The hypothesis was tested by the research group of Bruce Walker at Massachusetts General Hospital but—after early indications of promise—the hoped for result of prolonged control of HIV after ART withdrawal was not achieved.  Since that time, the fate of the original Berlin patient has been somewhat mysterious, with some published papers suggesting he had been lost to follow up. One of the last public updates given was by Bruce Walker at the 2003 IAS conference in Paris; Walker noted he had visited Jessen en route to the meeting, and learned that the individual was maintaining good control of viral load, but also that it had turned out that he possessed the HLA B*57 allele that is strongly associated with elite control of HIV replication in the absence of treatment.

Yesterday the New England Journal of Medicine published a letter from Heiko Jessen, Todd Allen and Hendrik Streeck that provides an update on the case. Titled “How a Single Patient Influenced HIV Research - 15-Year Follow-up,” it reveals that the individual has mostly maintained a low viral load off ART in the intervening years, with a mean level of 2,812 copies and only one blip to 25,000 copies. CD4 T cell count has remained relatively stable with a mean of 729 cells although a figure accompanying the paper indicates there have been a couple of dips below 500 (one accompanying the viral load blip some time ago, and one quite recently). The letter also notes that the individual has the HLA B*57 allele and concludes: “Although the early initiation of treatment may have long-term benefits for certain patients, a likely explanation for control of viral replication in this patient is genetic background, regardless of intervention. Thus, this case represents a cautionary tale of drawing broad conclusions from a single patient.”

Since not every HIV-positive person with the HLA B*57 allele becomes an elite controller, this conclusion is perhaps debatable, but it is impossible to know whether or not this individual would have ultimately maintained a low viral load even without the short course of ART. What is certain is that he is not cured of HIV infection. Unfortunately there may be some confusion about this because a forthcoming book is promoting the idea that, along with Timothy Brown, the original Berlin patient is, in fact, cured. Although there is some uncertainty about the appropriate application of the term “functional cure,” there is no definition that allows for persistently detectable HIV viral load. The commonly used terminology for cases like that of the first Berlin patient (as has been applied to members of the VISCONTI cohort) is "post treatment controller" or "virological remission." Extended follow up will be required to define to what extent individuals in this situation are protected from disease progression. 

First Human Trial of AAV as a Delivery Vehicle for HIV Neutralizing Antibodies Gets Underway

Over the past few years there has been growing interest in the use of adeno-associated virus (AAV) as a vehicle for generating anti-HIV neutralizing antibodies in humans. The approach is different from traditional vaccination, in that AAV is used essentially as a gene therapy: the AAV vector is designed to take up residence in cells and then act as a factory for churning out broadly neutralizing antibodies against HIV (genes that encode these antibodies are inserted into the vector). This novel idea may be able to circumvent the challenging problem of inducing the production of broadly neutralizing antibodies with traditional vaccines, and could potentially offer significant protection against HIV acquisition. 

As covered previously on the blog, there are two main research groups working on AAV-based HIV prevention. The laboratory of David Baltimore has named their approach vectored immunoprophylaxis (VIP) and last Sunday they published a study in Nature Medicine demonstrating protection against vaginal HIV transmission in a humanized mouse model (the study was supported by the National Institute of Allergy and Infectious Diseases, who issued a press release drawing attention to the findings). Meanwhile Philip Johnson and colleagues at the Children’s Hospital of Philadelphia are collaborating with the International AIDS Vaccine Initiative (IAVI) on a phase I clinical trial of an AAV vector encoding the HIV neutralizing antibody PG9, and, according to clinicaltrials.gov, the trial started recruiting participants last month. This is a major milestone for the research, as there were many challenges associated with obtaining regulatory approval for a human trial and Johnson and IAVI have been working toward this goal for many years. The estimated date for completion of the study is January 2016. 

Nature Medicine (2014) doi:10.1038/nm.3471

Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission

Alejandro B Balazs, Yong Ouyang, Christin M Hong, Joyce Chen, Steven M Nguyen, Dinesh S Rao, Dong Sung An & David Baltimore

Received 03 October 2013 Accepted 07 January 2014 Published online 09 February 2014

The vast majority of new HIV infections result from relatively inefficient transmission of the virus across mucosal surfaces during sexual intercourse. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza and human papilloma virus. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.

Poor CD4 T Cell Recovery Despite HIV Suppression Linked to Increased Morbidity and Mortality

A subset of HIV-positive people who initiate antiretroviral therapy (ART) and achieve suppression of HIV replication experience poor recovery of CD4 T cell numbers. Terms used to describe this subset of individuals include “discordant responders” and “immunological non-responders” (INRs). As yet, there is no universally accepted definition of INRs and a variety of CD4 T cell thresholds are cited in the scientific literature (e.g. persistently below 200, 250 or 350 cells despite HIV suppression). Depending on the definition, estimates of the proportion of people starting ART who can be categorized as INRs are typically around 5-20%. In studies conducted to date, the most consistently reported risk factors for this outcome are low CD4 T cell counts at the time of ART initiation and older age. Several published studies have also reported that INRs have a greater risk of morbidity and mortality compared to HIV-positive individuals with more robust CD4 T cell gains.

Two new papers now add to the evidence that INRs face an increased risk of illness and death. Frederik N. Engsig and colleagues conducted what may be the largest evaluation of the clinical impact of blunted CD4 recovery on ART, using data from participants in the Antiretroviral Therapy Cohort Collaboration (ART-CC) and the Collaboration of Observational HIV Research Europe (COHERE). The study was published on January 22nd in Clinical Infectious Diseases. A total of 5,550 individuals were identified who had a CD4 T cell count of less than 200 at the time of achieving viral suppression and data available for analysis after three years of follow-up. Out of this group, 835 (15%) did not experience recovery of CD4 T cells to over 200 cells. The greatest risk for this outcome was among those aged over 50 and those with the lowest CD4 T cell counts at the time when viral load was initially suppressed. Mortality risk in this group was significantly increased compared to the participants whose CD4 T cell counts rose above 200 cells, with a hazard ratio of 2.60 (95% confidence interval 1.86-3.81) - a 2.6-fold increase in risk. The estimated 5-year cumulative mortality was 11.8% in those with CD4 counts <200 cells at the end of the follow up period compared with 4.1%, 2.2% and 2.2% in those with CD4 counts of 201-350, 351-500 and >500 cells, respectively. The researchers note that these results are in accordance with two prior smaller studies, which reported a 2.69-fold and 3.4-fold greater risk of mortality among INRs.

The second paper, published in PLoS One, involves an analysis of the EuroSIDA cohort by Alexander Zoufaly and colleagues. The criteria for designating INRs in this study was different, being based on the lack of a CD4 T cell increase from the baseline measurement among a cohort starting with 350 cells or less (rather than the failure to crest a specific threshold). A statistically significant, close to 2-fold increase in the risk of fatal and non-fatal non-AIDS events was documented, although when the analysis was adjusted to take into account current CD4 T cell count this was attenuated to a statistical trend suggesting a 1.43-fold increase. Notably, the researchers point out that the elevated risk did not appear to diminish with longer duration of viral suppression. The smaller difference in risk found in this study is likely related to the difference in definition of INRs, and the fact that the majority of participants were in the 200-350 CD4 T cell range at the starting point for the analysis. 

The authors of both papers highlight the current lack of any interventions to reduce the risk of morbidity and mortality among INRs. Engsig and colleagues write: “since 15% of treated HIV positive individuals have CD4 count <200 cells/μl after long-term viral suppression, prognosis of such patients is a major concern… virally suppressed patients with low CD4 counts should be monitored closely for diseases not conventionally considered HIV-related, especially non-AIDS defining cancers and liver diseases.” On the subject of potential therapies, the Zoufaly paper adds: “to date, strategies to directly influence immune reconstitution by adding interleukin-2 or by modifying cART regimens have failed to show benefit over viral suppression alone; therefore new strategies perhaps aiming at other mechanisms to boost functional CD4 cells or decreasing the levels of immune-activation (e.g. interleukin-7, probiotics) need to be tested in people who show incomplete immune reconstitution despite sustained viral suppression.”

Unfortunately, as noted yesterday in the post on CD4/CD8 ratios, a clinical evaluation of IL-7 in INRs appears unlikely to happen anytime soon due to the recent bankruptcy of the original manufacturer. TAG maintains a listing of clinical trials for people with suboptimal immune reconstitution despite HIV suppression, derived from the clinicaltrials.gov database, but currently the page offers a dismayingly limited array of options: there are a total of seven trials, and in only one case is there a smidgeon of published evidence that the intervention could be beneficial. And that intervention, umbilical cord mesenchymal stem cells, does not seem well suited to large-scale manufacturing. There is certainly interest in the scientific community in pursuing studies of new approaches, including a variety of anti-inflammatory/anti-immune activation strategies and probiotic/prebiotic combinations (based on promising findings in macaques), but the current research funding environment is certainly not helping efforts to translate these ideas into the clinic. Recent updates from the National Institutes of Health indicate that paylines for research grants are at historic lows: for established investigators, only the top 8% of grant proposals are being funded, and for new investigators, the top 12%. The consequences of a slowdown in scientific progress will be profound, and INRs are an example of a population with a great deal at stake.

Clin Infect Dis. (2014) doi: 10.1093/cid/ciu038

First published online: January 22, 2014

Long-term mortality in HIV positive individuals virally suppressed for more than three years with incomplete CD4 recovery

Frederik N. Engsig1,2, Robert Zangerle3, Olga Katsarou4, Francois Dabis5, Peter Reiss6, John Gill7, Kholoud Porter8, Caroline Sabin9, Andrew Riordan10, Gerd Fätkenheuer11, Félix Gutiérrez12, Francois Raffi13, Ole Kirk1,14, Murielle Mary-Krause15, Christoph Stephan16, Patricia Garcia de Olalla17, Jodie Guest18, Hasina Samji19, Antonella Castagna20, Antonella d'Arminio Monforte21, Adriane Skaletz-Rorowski22, Jose Ramos23, Giuseppe Lapadula24, Cristina Mussini25, Lluís Force26, Laurence Meyer27, Fiona Lampe28, Faroudy Boufassa29, Heiner C. Bucher30, Stéphane De Wit31, Greer A. Burkholder32, Ramon Teira33, Amy C. Justice34,35, Tim R. Sterling36, Heidi Crane37, Jan Gerstoft1, Jesper Grarup14, Margaret May38, Geneviève Chêne5, Suzanne M. Ingle38, Jonathan Sterne38, Niels Obel1, The Antiretroviral Therapy Cohort Collaboration (ART-CC) and the Collaboration of Observational HIV Research Europe (COHERE) in EuroCoord

Abstract

Background. Some HIV infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/µL after three years of sustained viral suppression and (2) the association of achieved CD4 count with subsequent mortality.

Methods. We included treated HIV infected adults from two large international HIV cohorts, who were virally suppressed (≤500 HIV-1 RNA copies/ml) for >3 years with CD4 count ≤200 cells/µL at start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality.

Results. Of 5550 eligible individuals, 835 (15%) did not reach CD4 count >200 cells/µL after three years of suppression. Increasing age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998 and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving CD4 count >200 cells/µL. Individuals with CD4 ≤200 cells/µL after three years of viral suppression had substantially increased mortality (adjusted hazard ratio 2.60; 95% confidence interval 1.86-3.61) compared to those who achieved CD4 count >200 cells/µL. The increased mortality was seen across different patient groups and for all causes of death.

Conclusions. Virally suppressed HIV positive individuals on cART who do not achieve CD4 count >200 cells/µL have substantially increased long-term mortality.

PLoS ONE 9(1): e87160. doi:10.1371/journal.pone.0087160

Immuno-Virological Discordance and the Risk of Non-AIDS and AIDS Events in a Large Observational Cohort of HIV-Patients in Europe

Alexander Zoufaly, Alessandro Cozzi-Lepri, Joanne Reekie, Ole Kirk, Jens Lundgren, Peter Reiss, Djordje Jevtovic, Ladislav Machala, Robert Zangerle, Amanda Mocroft, Jan Van Lunzen, EuroSIDA in EuroCoord

Published: January 31, 2014DOI: 10.1371/journal.pone.0087160

Abstract

Background

The impact of immunosuppression despite virological suppression (immuno-virological discordance, ID) on the risk of developing fatal and non-fatal AIDS/non-AIDS events is unclear and remains to be elucidated.

Methods

Patients in EuroSIDA starting at least 1 new antiretroviral drug with CD4<350 cells/µl and viral load (VL)>500 copies/mL were followed-up from the first day of VL< = 50 copies/ml until a new fatal/non-fatal non-AIDS/AIDS event. Considered non-AIDS events included non-AIDS malignancies, pancreatitis, severe liver disease with hepatic encephalopathy (>grade 3), cardio- and cerebrovascular events, and end-stage renal disease. Patients were classified over time according to whether current CD4 count was above (non-ID) or below (ID) baseline level. Relative rates (RR) of events were calculated for ID vs. non-ID using adjusted Poisson regression models.

Results

2,913 patients contributed 11,491 person-years for the analysis of non-AIDS. 241 pre-specified non-AIDS events (including 84 deaths) and 89 AIDS events (including 10 deaths) occurred. The RR of developing pre-specified non-AIDS events for ID vs. non-ID was 1.96 (95% CI 1.37–2.81, p<0.001) in unadjusted analysis and 1.43 (0.94–2.17, p = 0.095) after controlling for current CD4 count. ID was not associated with the risk of AIDS events (aRR 0.76, 95% CI 0.41–1.38, p = 0.361).

Conclusion

Compared to CD4 responders, patients with immuno-virological discordance may be at increased risk of developing non-AIDS events. Further studies are warranted to establish whether in patients with ID, strategies to directly modify CD4 count response may be needed besides the use of ART.

The Relevance of the CD4/CD8 Ratio in the Antiretroviral Therapy Era

An inversion of the normal ratio between CD4 and CD8 T cells was noted in the very first case reports of individuals with AIDS, before HIV was even identified. Although a number of studies subsequently reported an association between the CD4/CD8 ratio and risk of disease progression, CD4 T cell counts were more extensively researched and became the most commonly used surrogate marker of immune system health in HIV-positive people. In recent years, data has emerged from cohort studies of very elderly HIV-negative people indicating that, in this population, the CD4/CD8 ratio is a strong predictor of the risk of aging-associated diseases and mortality. This new information prompted the research group of Sergio Serrano-Villar at the University Hospital Ramón y Cajal in Madrid to evaluate whether measurement of the CD4/CD8 ratio may provide information about the risk of morbidity and mortality in HIV-positive people in the current era of antiretroviral therapy (ART).

Last year, Serrano-Villar and colleagues published preliminary studies showing associations between the CD4/CD8 ratio and levels of immune activation and markers of immune system aging (immunosenescence) in HIV infection. In two new papers published in HIV Medicine and PLoS One, they now extend these findings and report statistically significant associations between the CD4/CD8 ratio and markers of age-associated disease and the clinical outcomes of non-AIDS-related morbidity and mortality in HIV-positive people. The PLoS One study assesses the link between the CD4/CD8 ratio and several dissimilar non-AIDS diseases in people on ART, and reports a significant association in each case. Separate analyses of participants with low CD4 nadirs (<200 cells) and those with good CD4 recovery on ART (to >350 cells) find that CD4/CD8 ratios remain independently associated with non-AIDS events in each subgroup.

In discussing the implications of their findings, the researchers write: “patients with failure to increase the CD4/CD8 ratio despite achieving full immunovirological response to ART might benefit from screening programs and aggressive management of concomitant risk factors for age-associated disease.” They also note that, since there appears to be a relationship between immune activation and the CD4/CD8 ratio, such individuals may be prime candidates for inclusion in clinical trials of interventions that aim to reduce immune activation and associated adverse clinical outcomes. However, several limitations to the study are acknowledged, and the authors stress that: “before using the CD4/CD8 ratio as a surrogate of serious non-AIDS-related illnesses, these results should be reproduced in larger and prospective studies.”

As it currently stands, there are very few reports of therapies capable of improving low CD4/CD8 ratios in HIV-positive people on ART. IL-7 increases both CD4 and CD8 T cell numbers, and according to a new study published in PLoS Pathogens, may reduce markers of inflammation, but the clinical impact of this cytokine has yet to be evaluated. A further complication is that the company behind IL-7, Cytheris, recently went bankrupt, leaving the rights to its development for HIV in the hands of the French Agence Nationale de Recherche sur le SIDA (ANRS) and a small biotech named Cognate Biosciences. SB-728-T, a gene therapy under development by Sangamo Biosciences, has been reported to significantly improve CD4/CD8 ratios in people on ART, but the duration of the effect is unclear and the company appears uninterested in developing the approach for people with suboptimal immune reconstitution (their focus is on attempting to achieve control of HIV replication after ART interruption). The therapy is also complex to administer because it involves the extraction, expansion and genetic modification of CD4 T cells, followed by reinfusion. A letter from TAG and many other community activists and organizations asking the company to continue to study the potential of SB-728-T to promote immune reconstitution fell on deaf ears.

Although not directly connected to the work of Sergio Serrano-Villar and colleagues, another study on the topic of the CD4/CD8 ratio in HIV infection was published online by the Journal of Immunology this past Monday. Marcus Buggert and a Swedish research team used a bioinformatics approach to explore the connections between several of the laboratory measures used to monitor HIV disease progression (including CD4 count and CD4/CD8 ratio) and a large suite of T cell markers that are perturbed by HIV infection (including activation, exhaustion and immunosenescence markers). Focusing primarily on untreated HIV infection, the researchers find that the CD4/CD8 ratio is the best predictor of the combined pathological changes to the T cell immune system that occur in HIV-positive people compared to uninfected controls. The paper concludes: “these findings are of particular interest to future therapy or cure studies, in which simple measurements are required to monitor ongoing pathological events of the T cell repertoire in HIV-infected subjects.”

HIV Med. 2014 Jan;15(1):40-9. doi: 10.1111/hiv.12081. Epub 2013 Sep 6.

The CD4:CD8 ratio is associated with markers of age-associated disease in virally suppressed HIV-infected patients with immunological recovery.

Serrano-Villar S, Moreno S, Fuentes-Ferrer M, Sánchez-Marcos C, Avila M, Sainz T, de Villar NG, Fernández-Cruz A, Estrada V. 

Abstract

OBJECTIVES: Inversion of the CD4:CD8 ratio (< 1) has been identified as a hallmark of inmmunosenescence and an independent predictor of mortality in the general population. We aimed to assess the association between the CD4:CD8 ratio and markers of age-associated disease in treated HIV-infected patients with good immunovirological response.

METHODS: A cross-sectional analysis was conducted in 132 HIV-infected adults on antiretroviral therapy (ART), with plasma HIV RNA < 50 HIV-1 RNA copies/mL for at least 1 year, CD4 count > 350 cells/μL and age < 65 years. We analysed the associations between the CD4:CD8 ratio and subclinical atherosclerosis [assessed using carotid intima-media thickness (IMT)], arterial stiffness [assessed using the augmentation index (AIx)], the estimated glomerular filtration rate (eGFR), muscle wasting and sarcopenia [assessed using appendicular lean mass/height(2) (ALM) measured by dual-energy X-ray absorptiometry (DEXA)].

RESULTS: CD4:CD8 ratio inversion was associated with higher IMT, lower eGFR and lower ALM (all values P < 0.05), but not with AIx. In multivariate analyses adjusted for age, sex, hypertriglyceridaemia, tobacco use and cumulative ART exposure, inversion of the CD4:CD8 ratio was independently associated with higher IMT [odds ratio (OR) 2.9; 95% confidence interval (CI) 1.2-7.1], arterial stiffness (OR 4.8; 95% CI 1.0-23.5) and lower eGFR (OR 5.2; 95% CI 1.0-64.4), but not sarcopenia (OR 0.7; 95% CI 0.2-2.7). These associations persisted when models were applied to subjects with nadir CD4 counts > 200 cells/μL and those with CD4 counts > 500 cells/μL.

CONCLUSIONS: The CD4:CD8 ratio in treated HIV-infected subjects with good immunovirological response is independently associated with markers of age-associated disease. Hence, it might be a clinically useful predictor of non-AIDS-defining conditions.

PLoS ONE 9(1): e85798. doi:10.1371/journal.pone.0085798 

Increased Risk of Serious Non-AIDS-Related Events in HIV-Infected Subjects on Antiretroviral Therapy Associated with a Low CD4/CD8 Ratio

Sergio Serrano-Villar, María Jesús Pérez-Elías, Fernando Dronda, José Luis Casado, Ana Moreno, Ana Royuela, José Antonio Pérez-Molina, Talia Sainz, Enrique Navas, José Manuel Hermida, Carmen Quereda, Santiago Moreno

Published: January 30, 2014DOI: 10.1371/journal.pone.0085798 

Abstract

Background

A low CD4/CD8 ratio has been identified in the general population as a hallmark of inmmunosenescence and a surrogate of all-cause mortality. We aimed to investigate in treated HIV-infected individuals the relationship between the CD4/CD8 ratio and serious non-AIDS events.

Methods

Case-control study within a prospective hospital-based cohort of HIV-infected subjects during at least one year of ART-mediated viral suppression. Cases were patients with serious non-AIDS events (non-AIDS malignancies, cardiovascular disease, and end-stage kidney disease), and controls individuals who did not developed non-AIDS events during follow-up. Data were analyzed using ROC analysis and multivariate logistic regression. Conditional logistic regression was performed in 200 cases/controls matched by age, sex, nadir CD4 and proximal CD4 counts.

Results

We analyzed 407 subjects (109 cases, 298 controls). The CD4/CD8 ratio was lower in cases (0.44 vs. 0.70, P<0.0001), with higher discriminatory ability for the detection of non-AIDS events than the CD4 count, CD8 count and nadir CD4. Multivariate analyses (adjusted for age, sex, nadir CD4, proximal CD4 count, year of ART initiation and ART duration) confirmed the independent association of a low CD4/CD8 ratio with the risk of non-AIDS morbidity (per CD4/CD8 ratio quartile decrease, OR, 2.9; 95% CI, 1.3–6.2) and non-AIDS mortality (OR, 2.8; 95% CI, 1.5–5.3).

Conclusions

The CD4/CD8 ratio provides additional information to the CD4 counts and nadir CD4 in treated HIV-infected individuals, since it is independently associated with the risk of non-AIDS-related morbidity and mortality. This association is robust and maintained within different subgroups of patients.

The Journal of Immunology

Published online before print February 3, 2014, doi: 10.4049/​jimmunol.1302596

Multiparametric Bioinformatics Distinguish the CD4/CD8 Ratio as a Suitable Laboratory Predictor of Combined T Cell Pathogenesis in HIV Infection

Marcus Buggert, Juliet Frederiksen, Kajsa Noyan, Jenny Svärd, Babilonia Barqasho, Anders Sönnerborg, Ole Lund, Piotr Nowak, and Annika C. Karlsson

Abstract

HIV disease progression is characterized by numerous pathological changes of the cellular immune system. Still, the CD4 cell count and viral load represent the laboratory parameters that are most commonly used in the clinic to determine the disease progression. In this study, we conducted an interdisciplinary investigation to determine which laboratory parameters (viral load, CD4 count, CD8 count, CD4 %, CD8 %, CD4/CD8) are most strongly associated with pathological changes of the immune system. Multiparametric flow cytometry was used to assess markers of CD4+ and CD8+ T cell activation (CD38, HLA-DR), exhaustion (PD-1, Tim-3), senescence (CD28, CD57), and memory differentiation (CD45RO, CD27) in a cohort of 47 untreated HIV-infected individuals. Using bioinformatical methods, we identified 139 unique populations, representing the “combined T cell pathogenesis,” which significantly differed between the HIV-infected individuals and healthy control subjects. CD38, HLA-DR, and PD-1 were particularly expressed within these unique T cell populations. The CD4/CD8 ratio was correlated with more pathological T cell populations (n = 10) and had a significantly higher average correlation coefficient than any other laboratory parameters. We also reduced the dimensionalities of the 139-unique populations by Z-transformations and principal component analysis, which still identified the CD4/CD8 ratio as the preeminent surrogate of combined T cell pathogenesis. Importantly, the CD4/CD8 ratio at baseline was shown to be significantly associated with CD4 recovery 2 y after therapy initiation. These results indicate that the CD4/CD8 ratio would be a suitable laboratory predictor in future clinical and therapeutic settings to monitor pathological T cell events in HIV infection.