TAG HIV Basic Science, Vaccines, and Cure Project Blog

Webcasts and Abstracts from the AIDS Vaccine 2012 Conference

The AIDS Vaccine 2012 conference took place in Boston September 9–12, organized by the Global HIV/AIDS Vaccine Enterprise, the Ragon Institute of MGH, MIT and Harvard, and the Havard Center for AIDS Research. Webcasts of all the conference sessions are now available online, and the abstracts have been posted as a a supplement to the open-access journal Retrovirology. Topics of discussion included follow-up from the RV144 Thai vaccine trial (including recently published evidence that protection may have been limited to HIV variants with specific genetic sequences in the V2 region of the viral envelope), new approaches to the induction of broadly neutralizing antibodies, the potential importance of a recently identified CD4 T-cell subset named T follicular helper cells, and opportunities for synergy between vaccine research and efforts to cure HIV infection.

Of relevance to the latter topic, Louis Picker presented an update on his studies using a CMV vector to immunize against the highly virulent SIVmac239 in rhesus macaques. Picker's previously published work had suggested that some immunized animals in these studies were progressively clearing SIVmac239 infection, and he showed additional evidence that this is the case. Three animals have now been euthanized after long periods of follow-up (485 to over 1,160 days postchallenge) and analyzed intensively for evidence of SIVmac239 infection. All three had controlled SIVmac239 to undetectable levels with only small blips in viral load seen shortly after challenge; at the time of necropsy no viral load blips had been observed for around 1.5–2 years. No replication-competent SIVmac239 could be detected in any animal, and PCR testing could find viral DNA and RNA only in a limited number of tissues, at extremely low background levels (comparable to PCR results obtained from control animals never exposed to SIVmac239). Picker noted that these findings are unprecedented and may challenge the generally accepted wisdom that lentiviral infections cannot be cleared. He also highlighted the implications for cure research, stating that a study is now under way that will evaluate the CMV vector as a therapeutic vaccine in ART-treated rhesus macaques chronically infected with SIVmac239. In parallel, an ongoing collaboration between Picker's laboratory and the Vaccine & Gene Therapy Institute in Florida is working to design CMV vectors for human trials. 

Quantifying HIV-1 Exposure to Illuminate Resistance to Infection

In the early 1990s, the research group of Frank Plummer at the University of Manitoba drew considerable attention—and some controversy—when they reported that, among a large cohort of female sex workers in Nairobi, a subset showed evidence of resistance to HIV infection. The evidence emerged over the course of a long-term study that found that women starting sex work faced a very high risk of seroconverting in the first two years. However, for a subset of women who remained HIV-negative, the risk of becoming infected subsequently declined significantly over time, which Plummer and colleagues interpreted as evidence of resistance to acquisition. Despite initial skepticism, the findings prompted efforts to identify individuals with possible resistance to HIV in other settings, such as among serodiscordant couples (in which one partner is HIV-positive and the other HIV-negative). There is now a substantial amount of literature on the topic, as well as ongoing workshops and research collaborations, but one of the challenges in the field is that there are no widely accepted criteria for defining high exposure to HIV (an important part of assessing whether an individual may be resistant as opposed to simply unexposed).

In a new paper in the Journal of Infectious Diseases, Romel Mackelprang and colleagues from the Partners in Prevention HSV/HIV Transmission Study describe a method for quantifying HIV exposure among serodiscordant couples, with the goal of enhancing efforts to identify individuals with potential resistance to infection. The study draws on data from a trial involving 3,408 serodiscordant heterosexual African couples. Risk factors that were associated with HIV transmission—such as unprotected sex, viral load level in the HIV-positive partner, and genital ulcer disease—were used to create “exposure scores” for the study participants. Unsurprisingly, high exposure was associated with a 6.9-fold increased risk of infection compared to low exposure. But these scores also identified a subset of 475 individuals with persistently high exposure who remained seronegative. Echoing Frank Plummer’s findings, the risk of HIV infection appeared to decline over the time in the high exposure group, while remaining constant among participants with lower exposure.

To further validate these findings, the researchers applied a simplified version of the exposure-score model to an independent cohort of 485 serodiscordant couples from Kampala, Uganda, and Soweto, South Africa. Again, the analysis identified a group (comprising 48 individuals) with high exposure but a decreasing risk of acquiring HIV infection over time. The study authors conclude: “our approach to estimating HIV-1 exposure using longitudinal data from both partners in HIV-1–serodiscordant couples provides an objective tool to identify subsets of HESN [HIV-1–exposed seronegative] individuals to target for identification of host factors protecting against HIV-1.” Additional details on the exposure scoring system are provided as supplementary data on the journal website.  

J Infect Dis. (2012)

doi: 10.1093/infdis/jis480

First published online: August 27, 2012

Quantifying Ongoing HIV-1 Exposure in HIV-1–Serodiscordant Couples to Identify Individuals With Potential Host Resistance to HIV-1

Romel D. Mackelprang1,2, Jared M. Baeten1,2,3, Deborah Donnell1,5, Connie Celum1,2,3, Carey Farquhar1,2,3, Guy de Bruyn7, Max Essex8,9, M. Juliana McElrath5,6, Edith Nakku-Joloba10, Jairam R. Lingappa1,3,4 and for the Partners in Prevention HSV/HIV Transmission Study Team

1 Department of Global Health

2 Department of Epidemiology

3 Department of Medicine

4 Department of Pediatrics, University of Washington

5 Statistical Center for HIV/AIDS Research and Prevention

6 The Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

7 Perinatal HIV Research Unit, University of the Witwatersrand, South Africa

8 Botswana-Harvard AIDS Institute Partnership, Gaborone, Botswana

9 Harvard School of Public Health, Boston, Massachusetts

10 School of Public Health, Makerere University, Kampala, Uganda

Abstract

Background. Immunogenetic correlates of resistance to HIV-1 in HIV-1–exposed seronegative (HESN) individuals with consistently high exposure may inform HIV-1 prevention strategies. We developed a novel approach for quantifying HIV-1 exposure to identify individuals remaining HIV-1 uninfected despite persistent high exposure.

Methods. We used longitudinal predictors of HIV-1 transmission in HIV-1 serodiscordant couples to score HIV-1 exposure and define HESN clusters with persistently high, low, and decreasing risk trajectories. The model was validated in an independent cohort of serodiscordant couples. We describe a statistical tool that can be applied to other HESN cohorts to identify individuals with high exposure to HIV-1.

Results. HIV-1 exposure was best quantified by frequency of unprotected sex with, plasma HIV-1 RNA levels among, and presence of genital ulcer disease among HIV-1–infected partners and by age, pregnancy status, herpes simplex virus 2 serostatus, and male circumcision status among HESN participants. Overall, 14% of HESN individuals persistently had high HIV-1 exposure and exhibited a declining incidence of HIV-1 infection over time.

Conclusions. A minority of HESN individuals from HIV-1–discordant couples had persistent high HIV-1 exposure over time. Decreasing incidence of infection in this group suggests these individuals were selected for resistance to HIV-1 and may be most appropriate for identifying biological correlates of natural host resistance to HIV-1 infection.