TAG HIV Basic Science, Vaccines, and Cure Project Blog

Finding International AIDS Conference Presentations Online

The XVIII International AIDS Conference took place last week in Vienna and many of the presentations are now available online. However, the conference website can be somewhat challenging to navigate and the location of slides and abstracts may not always be readily apparent. The first step is to download the Microsoft Silverlight plug-in that is required to use the programme-at-a-glance, where links to abstracts and slide presentations are located (a download button will automatically appear on this page if you do not have the plug-in). Once Silverlight is installed, all the sessions from each day of the conference can be browsed. Clicking on a session title opens up a slightly larger window with a “more info” link at the bottom right. Clicking on the “more info” link then brings you to the page containing the full details of that session, including all the presentation titles and abstracts. In many cases there is a “slides and audio” link to the presentation in Flash plug-in format. Although some presentation titles also have “Powerpoint” immediately to the left, do not get discouraged if nothing happens when you click this link; if you scroll further down the page, there is another section entitled “Powerpoints presentations” and clicking the links in this section will download the powerpoint slides.

As a short-cut, I’ve included direct links here to sessions relevant to basic science and biomedical prevention.

MOPDB1: Issues in HIV Therapy and Resistance, Oral Poster Discussion, Monday July 19, 1-2pm

MOSY05: Innate Immunity - Key to Control?, Symposium, Monday July 19, 2:30-4pm

MOAA01: Novel Therapeutic Strategies, Oral Abstract Session, Monday July 19, 4:30-6pm

TUSY02: Pathogenesis - The Battle of the Immune System, Symposium, Tuesday July 20, 11am-12:30pm

TUSS05: Safety and effectiveness of 1% Tenofovir Vaginal Microbicide Gel in South African Women: Results of the CAPRISA 004 Trial, Special Session, Tuesday July 20, 1-2pm

TUPDA1: Role of Dendritic Cells in HIV Infection, Oral Poster Discussion, Tuesday July 20, 1-2pm

TUSY06: HIV Vaccines - Quo Vadis?, Symposium, Tuesday July 20, 2:30-4pm

TUAA01: Advances in Vaccine Development, Oral Abstract Session, Tuesday July 20, 4:30-6pm

WEAA01: Correlates of Immune Protection, Oral Abstract Session, Wednesday July 21, 11am-12:30pm

WEPDA1: Viral Persistence and Latency, Oral Poster Discussion, Wednesday July 21, 1-2pm

WESY07: Use of Antiretrovirals for Prevention: PrEP, PEP and ART, Symposium, Wednesday July 21, 2:30-4pm

WEAA02: T-Cell Responses in HIV Infection, Oral Abstract Session, Wednesday July 21, 2:30-4pm

WEAA03: Immune Activation and Inflammation, Oral Abstract Session, Wednesday July 21, 4:30-6pm

THLBA1: Late Breaker Track A, Oral Abstract Session, Thursday July 22, 11am-12:30pm

THPDA1: Immune Dysfunctions, Oral Poster Discussion, Thursday July 22, 1-2pm

THAA01: Persistence of HIV Reservoirs, Oral Abstract Session, Thursday July 22, 2:30-4pm

THBS03: Understanding HIV Transmission Mechanisms: Microbicides and PrEP, Thursday July 22, 4:30-6pm

FRAX01: It All Starts Here: Acute HIV Infection, Friday July 23, 11am-12:30pm

FRAA01: Mechanisms of Transmission, Friday July 23, 11am-12:30pm

FRPL02: Rapporteur Session, Friday July 23, 1-3:15pm

Frequent Detection of Natural Human Adenovirus Infections

Adenoviruses are common in nature and are a major cause of severe colds. During the past decade, attenuated forms of adenovirus have become increasingly utilized as experimental vaccine vectors due to their targeting of dendritic cells and ability to induce CD8 T cell responses in the majority of recipients (no other vector to date has shown comparable CD8 T cell immunogenicity). Adenoviruses are categorized into a number of different serotypes, with serotype 5 (Ad5) being among the most prevalent. An HIV vaccine candidate that used Ad5 as a vector was developed by Merck, but failed to show efficacy and significantly enhanced HIV acquisition risk in a subset of trial participants with pre-existing antibody responses against natural Ad5.

Since the Merck data were published, there has been debate about the mechanism by which the Ad5 vector could have increased the risk of HIV acquisition, and even claims that the result was a statistical fluke or represented a confounding effect related to circumcision status (the former claim is possible, the latter was contradicted by a multivariate analysis showing that both lack of circumcision and receipt of the Ad5 vaccine were associated with an increased likelihood of HIV acquisition). Perhaps most controversially, it has been suggested that perhaps the Merck vector boosted Ad5-specific CD4 T cell responses, thus providing more activated CD4 T cell targets for HIV infection. Two studies that measured Ad5-specific CD4 T cell responses in recipients of the Merck vaccine based on cytokine production have argued against this possibility (see here and here), while another that assessed Ad5-specific CD4 T cell responses based on their ability to proliferate suggested that CD4 T cell-mediated enhancement could have played a role.

Lurking on the sidelines of this contentious debate has been the issue of natural adenovirus infection, about which relatively little is known. Now a study by Larry Corey’s research group, published recently in PLoS One, has for the first time evaluated natural adenovirus infections among one of the populations enrolled in the Merck HIV vaccine trial, Peruvian men who have sex with men (MSM).

The results are perhaps surprising: the majority of the 20 men studied had detectable adenovirus DNA in rectal swabs during follow-up; the average rate of detection at any given timepoint was in 30% of samples. A variety of adenovirus serotypes were represented, including Ad5, Ad26 and Ad48, all of which are in development as vaccine vectors. The study authors note that: “shedding typically occurred on consecutive days in clustered episodes lasting a median of 4 days (range 1 to 9 days) separated by periods without shedding, suggesting frequent new infections or reactivation of latent infections over time.”

The study raises a number of issues. First and foremost, it suggests that when a pathogen is being developed as a potential vaccine vector, a thorough understanding of the natural infection should be obtained early on in the research process, and not after the fact.  In the case of adenovirus vectors, their success in solving the difficult problem of inducing CD8 T cell responses may have caused the lack of information on natural infections to be somewhat overlooked. In terms of specific relevance to the Merck trial, the study implies that interactions between adenovirus-specific immunity and natural adenovirus infections are likely to be far more dynamic and ongoing than had previously been surmised. The boosting of Ad5-specific CD4 T cell responses by vaccination might therefore have different consequences depending on whether natural adenovirus infection is present, particularly given that the virus localizes in the mucosa and Ad5-specific CD4 T cell responses cross-react with a wide variety of serotypes. Additional studies will now be needed to investigate the impact of adenovirus-based vaccines on mucosal virus-specific CD4 T cell responses in the presence and absence of natural infection.

PLoS One. 2010 Jun 25;5(6):e11321.

Frequent detection of human adenovirus from the lower gastrointestinal tract in men who have sex with men.

Curlin ME, Huang ML, Lu X, Celum CL, Sanchez J, Selke S, Baeten JM, Zuckerman RA, Erdman DD, Corey L.

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

Abstract

BACKGROUND: The association between baseline seropositivity to human adenovirus (HAdV) type 5 and increased HIV acquisition in the Step HIV Vaccine Study has raised questions concerning frequency of acquired and/or persistent Adenovirus infections among adults at high risk of HIV-1 infection. METHODOLOGY: To evaluate the frequency and pattern of HAdV shedding from the lower GI tract, we retrospectively tested rectal swabs for HAdVs in a cohort of 20 HSV-2 positive HIV-positive Peruvian men who have sex with men (MSM) undergoing rectal swabbing three times/week for 18 consecutive weeks, in a prospective study of HSV-2 suppression in HIV infection. Viral DNA was extracted and amplified using a sensitive multiplex PCR assay that detects all currently recognized HAdV types. Molecular typing of viruses was performed on selected samples by hexon gene sequencing. Baseline neutralizing antibody titers to HAdVs -5, -26, -35 and -48 were also assessed. PRINCIPAL FINDINGS: 15/20 individuals had HAdV detected during follow up. The median frequency of HAdV detection was 30% of samples (range 2.0% to 64.7%). HAdV shedding typically occurred on consecutive days in clustered episodes lasting a median of 4 days (range 1 to 9 days) separated by periods without shedding, suggesting frequent new infections or reactivation of latent infections over time. 8 of the 15 shedders had more than one type detected in follow-up. 20 HAdV types from species B, C, and D were identified, including HAdV-5, -26 and -48, HAdV types under development as potential vaccine candidates. 14/20 subjects were seropositive for HAdV-5; 15/20 for HAdV-26; 3/20 for HAdV-35; and 2/20 for HAdV-48. HAdV shedding did not correlate with CD4 count, plasma HIV-1 viral load, or titers to HAdV-5 or HAdV-35. The sole individual with HAdV-5 shedding was HAdV-5 seropositive. CONCLUSIONS: HAdV shedding was highly prevalent and diverse, including types presently under consideration as HIV vaccine vectors. Subclinical HAdV infection of the GI tract is common among MSM in Peru; the prevalence of HAdV in the enteric tract should be evaluated in other populations. The association between ongoing recent enteric HAdV and the immune response to recombinant HAdV vaccines should be evaluated.

CAPRISA 004 Tenofovir Gel Microbicide Trial: Webcast of Presentations Now Online

The Kaiser Family Foundation has now posted a webcast of the CAPRISA 004 presentations that took place today at the XVIII International AIDS Conference in Vienna. 

A Standing Ovation for CAPRISA 004

Important additional details were presented at the International AIDS Conference today regarding the CAPRISA 004 tenofovir gel microbicide trial. The data provoked an emotional response from the audience, ultimately prompting a prolonged standing ovation. Salim Abdool Karim described the HSV-2 analysis, reporting that the 95% confidence intervals around the 51% efficacy result spanned 30-78% (p=.003). Several sensitivity analyses were also presented: adjustment for every known confounder (such as condom use) still showed efficacy of 47% (95% CI: 33-83%, p=.005) and considering four women with equivocal HSV-2 serology as infected only reduced the efficacy to 47% (95% CI 33-83%, p=.006).

Pharmacologist Angela Kashuba gave a talk outlining several significant associations between tenofovir concentrations and efficacy. Average drug levels in cervicovaginal fluid were significantly lower in women who acquired HIV compared to those who remained uninfected: 1 ng/mL (range: 0-290,734) compared to 520 ng/mL (0-1,338,079). The proportion of women with detectable levels was also significantly different between the two groups: 45% vs. 96%. For the HSV-2 efficacy analysis, there was a significant association between having a tenofovir level over 10,000 ng/mL; 24% of uninfected women were above this threshold compared to 6% that became HSV-2 positive. Kashuba addressed the issue of mechanism of action by stating that while the concentration of tenofovir required to inhibit HSV-2 in vitro is very high and not achievable with oral dosing, it can be obtained in tissues with gel administration.

Overall the presentations solidified the impression that the CAPRISA 004 results are robust and real. The pharmacology data is important and likely to offer crucial clues to improving the protective efficacy of the compound. The HSV-2 results may also have profound implications given the doubling in risk of HIV acquisition that is associated with HSV-2 seropositivity. Researcher Sheena McMormack nevertheless cautioned that there are some limitations; the lower bound of the confidence interval for the HIV result, at 6%, is not as high as is ideally desirable and CAPRISA 004 was a relatively small trial in a single population. But McMormack also stressed the need for rapid confirmation of the findings, because – as Salim Abdool Karim pointed out – the intervention could have the ability to prevent 1.3 million new infections and 800,000 deaths in South Africa alone. 

Microbicide Hope in Tenofovir Gel

The stubborn persistence and commitment of microbicide researchers, advocates and trial participants has finally seen some reward with positive results from a South African trial of the gel form of the antretroviral drug tenofovir. Originally due to be released on July 20th, the results were disclosed tonight after the UK Financial Times and two unnamed individuals who had been briefed on the findings apparently decided an exclusive story was more important than the normal ethical practice of honoring media embargoes. The news was quickly followed by official press releases and the publication of the paper describing the outcome of the trial – named CAPRISA 004 – in the journal Science. The lead authors are the wife-and-husband team of Quarraisha and Salim Abdool Karim.

Among a cohort of women at high risk of HIV infection followed for an average of 18 months, there were 38 infections in the group of 445 tenofovir gel recipients and 60 in the 444 placebo recipients. The HIV incidence rates were 5.6 per 100 women-years and 9.1 per 100 women-years, respectively, for an overall reduction in risk of 39% (95% confidence interval 6-60%). Efficacy was greater among the subgroup of women reporting high adherence to the gel with a 54% reduction in risk of HIV acquisition, albeit with an inevitably wider 95% confidence interval spanning 4-80% (the 95% confidence interval is a statistical assessment of the degree of uncertainty associated with the result). Although the data are not included in the Science paper, a fact sheet released by CAPRISA (Center for the AIDS Programme of Research in South Africa) and Family Health International reports that an analysis of HSV-2 incidence found a statistically significant 51% reduction in risk associated with receipt of tenofovir gel. The fact sheet notes that while several related compounds are known to have anti-HSV-2 activity, tenofovir has not been shown to be effective against the virus at standard doses, so the mechanism underlying this outcome remains to be clarified. The confidence intervals around the 51% efficacy against HSV-2 have not yet been reported but are likely to be made available when the official presentation of CAPRISA 004 is made at 1pm Central European Summer Time (7am EST) tomorrow at the 2010 International AIDS Conference. Further details about next steps and confirmatory trials should also emerge at that time. 

A huge number of media outlets have now picked up on the story and these articles can be found via Google news.

Published Online July 19, 2010

Science DOI: 10.1126/science.1193748

Science Express Index

RESEARCH ARTICLES

Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women

Quarraisha Abdool Karim,1,2,*, Salim S. Abdool Karim,1,2,3,* Janet A. Frohlich,1 Anneke C. Grobler,1 Cheryl Baxter,1 Leila E. Mansoor,1 Ayesha B. M. Kharsany,1 Sengeziwe Sibeko,1 Koleka P. Mlisana,1 Zaheen Omar,1 Tanuja N. Gengiah,1 Silvia Maarschalk,1 Natasha Arulappan,1 Mukelisiwe Mlotshwa,1 Lynn Morris,4 Douglas Taylor,5 on behalf of the CAPRISA 004 Trial Group

The CAPRISA 004 trial assessed effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445) with placebo gel (n = 444) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years, i.e., person time of study observation (38/680.6 women-years), compared to 9.1 per 100 women-years (60/660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence >80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence <50%), the HIV incidence reduction was 38% and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.

1 Centre for the AIDS Program of Research in South Africa (CAPRISA), Durban, South Africa.

2 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.

3 University of KwaZulu-Natal, Durban, South Africa.

4 National Institute for Communicable Diseases, Johannesburg, South Africa.

5 FHI, North Carolina, USA.

* These authors contributed equally to this work.

Published Online July 19, 2010

Science DOI: 10.1126/science.329.5990.374

Science Express Index

NEWS OF THE WEEK

At Last, Vaginal Gel Scores Victory Against HIV

Jon Cohen

For the first time ever, a vaginal gel has unequivocally blocked the transmission of HIV. In a trial that involved nearly 900 South African women, those who received a vaginal gel that contains an anti-HIV drug had a 39% lower chance of becoming infected by the virus than those who received a placebo. As reported today online in Science and in a presentation at the 18th International AIDS Conference in Vienna, of the 444 women who received a placebo gel, 60 became infected with HIV, versus 38 infections in the 445 women who received the microbicide. The result was statistically significant, and no serious side effects occurred.

Journal Supplements on HIV/AIDS

The new issue of the journal Nature has a free-access supplement on HIV/AIDS, including articles on a range of topics from immune activation to HIV/TB coinfection. Last week's issue of Science also features a special section including a series of articles on the epidemic in Eastern Europe by Jon Cohen and a review discussing prospects for a cure by Didier Trono, Carine Van Lint, Christine Rouzioux, Eric Verdin, Françoise Barré-Sinoussi, Tae-Wook Chun and Nicolas Chomont. The Science articles require a journal subscription. 

Genital Tract Immune Activation in Healthy Women from Kisumu, Kenya and San Francisco, USA

Over the years, an array of theories have been offered to explain the increased risk of heterosexual HIV transmission in sub-Saharan Africa compared to the US and Europe.  But these theories have almost exclusively focused on behavior, not biology. An example is the claim that concurrent sexual relationships are more common and account for higher HIV prevalence, which has achieved some popularity despite a lack of evidence to support it. Only a few studies have documented that background levels of immune activation are higher in sub-Saharan Africa, and suggested that this could contribute to an increased HIV transmission risk. And up until now, no research has specifically looked at immune activation in the genital tract.

A new paper by Craig Cohen and colleagues, just published in the journal AIDS, addresses this information gap. The authors start by noting that mucosal immune activation caused by genital tract infections (such as HSV-2) has been consistently associated with an increased risk of HIV acquisition. To address whether there might be geographic differences in background levels of immune activation in healthy women without any active infections, cervical samples from 18 women in San Francisco and 36 women in Kisumu were compared. Although the total number of CD4 cells in the samples were slightly higher in women from San Francisco, the number and proportion of activated CD4 T cells was significantly higher in the women from Kisumu (p value=<0.0001). Similar results were obtained when activated CD8 T cells were analyzed. The findings held true after controlling for multiple factors, including HPV status.

The authors conclude by stating: “Although other factors such as physical, behavioral, and structural conditions certainly put young women in sub-Saharan African at greater risk of HIV acquisition, ours is the first study to demonstrate that mucosal immune differences in the genital tract may also be important. In addition to stimulating further research, we believe that these findings should also start to dispel some of the preconceptions and stigma surrounding HIV acquisition among young women in sub-Saharan Africa.”

AIDS. 2010 Jun 25. [Epub ahead of print]

Increased levels of immune activation in the genital tract of healthy young women from sub-Saharan Africa.

Cohen CR, Moscicki AB, Scott ME, Ma Y, Shiboski S, Bukusi E, Daud I, Rebbapragada A, Brown J, Kaul R.

aDepartment of Obstetrics, Gynecology and Reproductive Sciences, USA bDepartment of Pediatrics, USA cDepartment of Biostatistics, University of California, San Francisco, California, USA dCenter for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya eDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada fDepartment of Epidemiology University of California, Los Angeles, California, USA.

Abstract

OBJECTIVES: To determine whether healthy, young women in sub-Saharan Africa have a more activated immune milieu in the genital tract (i.e. activated CD4 T cells) than a similar population in the United States. DESIGN:: A cross-sectional study nested in a phase 1 microbicide trial. METHODS: Cervical cytobrushes were collected from 18 to 24-year-old women in San Francisco, California, USA (n = 18) and Kisumu, Kenya (n = 36) at enrollment into a phase 1 microbicide trial. All participants tested negative for HIV, herpes simplex virus 2, gonorrhea, chlamydia, and trichomonas, and had abstained from sex for at least 7 days prior to enrollment. Cryopreserved T-cell populations were assayed by flow cytometry in a central laboratory. Secretory leukocyte protease inhibitor levels were assayed in cervicovaginal lavage samples. The Wilcoxon rank-sum test was used to compare immune parameters between sites. RESULTS: The total number of endocervical CD4 T cells was slightly higher in participants from San Francisco, but participants from Kisumu had a substantially higher number and proportion of CD4 T cells expressing the early activation marker CD69, with and without the HIV coreceptor C-C chemokine receptor type 5, and a greater proportion of activated CD8 T cells. Median (interquartile range) genital levels of secretory leukocyte protease inhibitor were lower in participants from Kisumu compared with those from San Francisco [190 (96-519) vs. 474 (206 817) pg/ml, P < 0.03]. CONCLUSION: Activated mucosal T cells were increased in the genital tract of young, sexually transmitted infection/HIV-free Kenyan women, independent of common genital coinfections, and secretory leukocyte protease inhibitor levels were reduced. The cause of these mucosal immune differences is not known, but could partly explain the high HIV incidence in young women from sub-Saharan Africa.

Community Viral Load Decline Associated with a Reduction in HIV Incidence

A study linking declines in the average viral load in San Francisco communities with reduced HIV incidence was published in PLoS One last month.  The lead author, Moupali Das-Douglas, presented the paper at CROI in February where it attracted some coverage, but the publication in PLoS appears to have flown beneath the media radar. The authors are careful to acknowledge that their data are associative, stating: “this is an observational study and there is limited ability to directly assess causality.” However, they argue that tracking viral loads at the community level can be a valuable health indicator, revealing disparities in access to healthcare services that need to be addressed. The authors also note that the documented decline in HIV infections occurred despite increases in other STDS, such as rectal gonorrhea, bolstering the case that viral load reductions rather than changes in risk behavior account for the findings.

The webcast of Moupali Das-Douglas’s CROI presentation is available on the conference website.  

PLoS One. 2010 Jun 10;5(6):e11068.

Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco.

Das M, Chu PL, Santos GM, Scheer S, Vittinghoff E, McFarland W, Colfax GN.

San Francisco Department of Public Health, San Francisco, California, USA.

Abstract

BACKGROUND: At the individual level, higher HIV viral load predicts sexual transmission risk. We evaluated San Francisco's community viral load (CVL) as a population level marker of HIV transmission risk. We hypothesized that the decrease in CVL in San Francisco from 2004-2008, corresponding with increased rates of HIV testing, antiretroviral therapy (ART) coverage and effectiveness, and population-level virologic suppression, would be associated with a reduction in new HIV infections. METHODOLOGY/PRINCIPAL FINDINGS: We used San Francisco's HIV/AIDS surveillance system to examine the trends in CVL. Mean CVL was calculated as the mean of the most recent viral load of all reported HIV-positive individuals in a particular community. Total CVL was defined as the sum of the most recent viral loads of all HIV-positive individuals in a particular community. We used Poisson models with robust standard errors to assess the relationships between the mean and total CVL and the primary outcome: annual numbers of newly diagnosed HIV cases. Both mean and total CVL decreased from 2004-2008 and were accompanied by decreases in new HIV diagnoses from 798 (2004) to 434 (2008). The mean (p = 0.003) and total CVL (p = 0.002) were significantly associated with new HIV cases from 2004-2008. CONCLUSIONS/SIGNIFICANCE: Reductions in CVL are associated with decreased HIV infections. Results suggest that wide-scale ART could reduce HIV transmission at the population level. Because CVL is temporally upstream of new HIV infections, jurisdictions should consider adding CVL to routine HIV surveillance to track the epidemic, allocate resources, and to evaluate the effectiveness of HIV prevention and treatment efforts.

The Broader They Come: Vaccine Research Center Reveals New Neutralizing Antibodies

Two papers published in Science Express today are receiving extensive coverage in the mainstream media. The studies, conducted by researchers at the NIH’s Vaccine Research Center (VRC), reveal the discovery of three new broadly neutralizing antibodies, one of which has activity against 91% of the viruses in a panel containing 190 different HIV variants from every known clade. The Wall Street Journal has an excellent article covering the research by Mark Schoofs. The antibodies are named VRC01, VRC02 and VRC03, and it is VRC01 that has the greatest breadth and potency of neutralization.

The work bears some similarities to the discovery of two broadly neutralizing antibodies reported last year by researchers associated with the International AIDS Vaccine Initiative (IAVI). Those antibodies, PG9 and PG16, neutralized around 70-80% of a similar panel of HIV variants. One important difference is that in the second paper published today, a VRC team led by Peter Kwong provides a detailed description of the target of VRC01 (the exact targets of PG9 and PG16 have not yet been uncovered). VRC01 targets a part of the HIV envelope protein that binds to the CD4 receptor, and the breadth of neutralization indicates that this part of the virus is highly conserved.

Kwong’s research group also looks in detail at the B cell responsible for making VRC01, which was sampled from an African American gay man with HIV infection. Importantly, the antibody-producing genes in the B cell do not appear to be rare or unusual, suggesting that it should be possible to prompt production of VRC01-like antibodies in uninfected people – if the right vaccine can be designed. However, the paper also shows that the B cell had undergone an unusually extensive process of “affinity maturation.” This process involves the stepwise accumulation of mutations (or deletions) in the B cell’s antibody-producing genes, resulting in the production of an antibody that is much better at glomming onto its target than the one the B cell started out producing. In fact, when the researchers reverted all the mutations that had occurred during affinity maturation (there were 66 in total), the antibody that was produced did not have any neutralizing activity.

In sum, the new VRC data appears to represent another significant step forward on the path toward an antibody-based HIV vaccine. It was once unclear whether broad neutralization of HIV by antibodies was possible at concentrations that could be achieved by vaccination, but the discovery of VRC01, PG9, PG16 and several other similarly potent candidates has addressed this uncertainty. The next challenge – and it is not insignificant – involves designing vaccines that can induce similar antibodies. In the case of VRC01, this will also require trying to recapitulate the complex process of B cell affinity maturation that led to the generation of the antibody. A more typical number of mutations associated with affinity maturation is around nine, so the 66 changes that led to the production of VRC01 may be a difficult path to retrace.

UPDATE: Heidi Ledford's story at Nature News provides additional information on the targeting and affinity maturation issues related to VRC01. 

Science Express, Published Online July 8, 2010

Science DOI: 10.1126/science.1187659

REPORTS

Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1

Xueling Wu,1,* Zhi-Yong Yang,1,* Yuxing Li,1,* Carl-Magnus Hogerkorp,1, William R. Schief,4 Michael S. Seaman,5 Tongqing Zhou,1 Stephen D. Schmidt,1 Lan Wu,1 Ling Xu,1 Nancy S. Longo,1 Krisha McKee,1 Sijy O’Dell,1 Mark K. Louder,1 Diane L. Wycuff,1 Yu Feng,1, Martha Nason,2 Nicole Doria-Rose,3 Mark Connors,3 Peter D. Kwong,1 Mario Roederer,1 Richard T. Wyatt,1,Gary J. Nabel,1, John R. Mascola1

Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1–infected subjects, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope (Env) structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of CD4 receptor binding. These probes were used to identify sera with NAbs to the CD4-binding site (CD4bs) and to isolate individual B cells from such an HIV-1–infected donor. By expressing immunoglobulin genes from individual cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of gp120, an important insight for future HIV-1 vaccine design.

1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

2 Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

3 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

4 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.

5 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

* These authors contributed equally to this work.

Science Express, Published Online July 8, 2010

Science DOI: 10.1126/science.1192819

RESEARCH ARTICLES

Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01

Tongqing Zhou,1 Ivelin Georgiev,1,* Xueling Wu,1,* Zhi-Yong Yang,1,* Kaifan Dai,1 Andrés Finzi,2 Young Do Kwon,1 Johannes Scheid,3 Wei Shi,1 Ling Xu,1 Yongping Yang,1 Jiang Zhu,1 Michel C. Nussenzweig,3 Joseph Sodroski,2,4 Lawrence Shapiro,1,5 Gary J. Nabel,1 John R. Mascola,1 Peter D. Kwong1

During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. Here, we determine the crystal structure of VRC01 in complex with an HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through V-gene–derived regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.

1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

2 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.

3 Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.

4 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

5 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.

* These authors contributed equally to this work.