The Acute HIV Infection Research Program at MGH

Two new studies reveal that a key phenomenon of an individual’s ability to control Hepatitis C Virus (HCV) is their ability to target critical regions of the virus. These studies, led by researchers at the Ragon Institute in collaboration with scientists at the Broad Institute and the University of Freiburg, appear in recent articles in the Journal of Virology and the journal Hepatology.  Efforts to develop vaccines against highly variable pathogens such as HIV and HCV have been thwarted in large part due to the ability of these viruses to rapidly mutate to avoid host immune responses. However, certain individuals are able to uniquely control each pathogen through proteins that orchestrate host immunity (termed HLA-B57 and HLA-B27).  In these studies, individuals expressing the protective alleles HLA-B57 or HLA-B27 were both found to elicit immune responses against regions of the HCV polymerase protein that are critical to the ability of the virus to replicate. These immune responses force the virus to develop highly deleterious escape mutations that significantly impair virus replication, even resulting in the development of secondary ‘compensatory’ mutations by the virus in an attempt to minimize the effects of these escape mutations. Importantly, HLA-B57 and HLA-B27 function to control HIV through a similar mechanism of selecting for highly deleterious mutations in critical regions of HIV.  Efforts are underway at the Ragon Institute to harness these findings to develop and test novel vaccine approaches against each of these human pathogens for which vaccines are still unavailable.

 

Link to Journal of Virology Abstract

 

Link to Hepatology Article

 

 

The Early Capture HIV Cohort Study (ECHO)

The identification of individuals with very acute HIV-1 infection, just days after exposure to HIV-1, is critical for a better understanding of the earliest events that occur following HIV-1 acquisition. The MHRP RV217 protocol, Early Capture HIV Cohort (ECHO), implemented a unique approach for acute HIV-1 infection diagnosis.  This study is based in populations in Thailand, Uganda, Kenya and Tanzania with the hope to study HIV-1 prevalence, incidence, host genetics and viral diversity in acute HIV-1 infection. The goal is to enroll 150 individuals with acute infection within the 3-5 days of exposure to HIV-1 (Fiebig stages I-III).

The study population is followed for two years and consists of individuals who are thought to be at high risk for HIV-1 infection. Throughout the study, these high risk individuals provide blood samples by finger stick twice a week in microvette vials. Using the very sensitive technique of Gen-Probe’s HIV RNA Assay, the blood samples are then used to test for the presence of HIV-1 RNA. The ability to obtain samples during the antibody negative stage provides the opportunity to study the early viral evolution and its relation to innate immunity.

Several studies have suggested that events occurring in very early acute HIV-1 infection influence the ultimate control of viremia and the prognosis of the disease. ECHO provides the opportunity for classification of the founding virus and the understanding of host control among these high risk individuals. This cohort will be followed up for two years which will provide data on the level of viral replication and decline of CD4+ T cell numbers. It also gives researchers the opportunity to determine the relationship between early immunological and virological events, viral load set point and clinical outcome throughout the acute and early phase of the infection. These data will be very relevant for vaccine design.

AIDS Vaccine Conference 2011

Features Oral and Poster Presentations from Ragon Institute's Acute P01 Investigators

The 2011 AIDS Vaccine conference, held in Bangkok, Thailand, was organized by the Global HIV Vaccine Enterprise, a collaboration in an effort to advance HIV vaccine research. This conference is the largest scientific meeting, which focuses exclusively on HIV vaccine research and annually brings together scientists from across the world engaged in AIDS vaccine research and development. The conference featured oral and poster presentations by a number of investigators from the Ragon Institute who participate in the effort to develop a protective HIV-1 vaccine. These included several presentations by investigators involved in the Acute HIV-1 Infection research efforts at the Ragon Institute that are directly supported by an NIH Program Project Grant.  Below we have listed these oral and poster presentations: 

Symposia:

Antiviral Activity of NK Cells in HIV-1 Infection
Marcus Altfeld

Oral Abstracts

Identification of Escape-Refractory Subdominant CD8 Epitopes for Common HLA Alleles CL Boutwell, C Oniangue-Ndza, A Schneidewind, H Streeck, A Seese, E Mellors, K Murthy, K Power, M Kemper, T Dudek, BD Walker, M Altfeld, TM Allen

HIV-Specific Cytolytic CD4+ T-Cell Responses During Acute HIV-1 Infection Predict Disease Outcome DZ Soghoian, H Jessen, S Cutler, M Flanders, S Ranasinghe, M Lindqvist, I Davis, K Lane, J Rychert, ES Rosenberg, BD Walker, H Streeck

Important Contribution of Subdominant HIV-Specific CD8 T Cell Responses to Early Control of HIV Replication  Streeck, D Kwon, M Addo, M Flanders, I Davis, S Cutler, J Rychert, K Lane, B Yassine-Diab, J Routy, S Little, H Jessen, A Kelleher, F Hecht, R Sekaly, E Rosenberg, B Walker, T Allen, M Altfeld

Frequent and Strong NK Responses to HIV-1 Env Peptides in Individuals with Acute and Chronic HIV-1 Infection CF Thobakgale, L. Fadda, K. Lane, F. Pereyra, B.D. Walker, T. Allen, M. Altfeld

Poster Sessions:

Differential Regulation of Various TLR Pathways in Acute and Chronic HIV-1 Infection J Chang, A Lacas, RJ Lindsay, E Doyle, K Axten, BD Walker, F Pereyra, T Allen, M Altfeld

Different Cytokine Profiles Induced by HIV-1 and HIV-1-Derived TLR Ligands in Monocytes and mDCs RP Simmons, E Groden, JJ Chang, R Lindsay, L Fadda, JD Lifson, K Lane, K Axten, E Rosenberg, T Allen, M Altfeld

Dysregulation of Tim-3 Expression on NK Cells in Chronic HIV-1 Infection S Jost, UY Moreno-Nieves, J Reardon, I Toth, A Piechocka-Trocha, G Alter, M Altfeld, MM Addo

Increased Plasma Levels of Hemoxygenase-1 (HO-1) and Presence of HO-1-Specific Regulatory T Cells in Acute HIV-1 Infection M Angin, A Fathi, M King, MM Addo

Preexposure Prophylaxis Reduces HIV Acquisition

A recent study has found that the use of preexposure antiviral treatment (termed preexposure prophylaxis or "PrEp") can be highly successful in preventing HIV infection in men-who-have-sex-with-men (MSM). Dr. Ken Mayer, Medical Research Director and Co-chair of the Fenway Institute, is one of the Principal Investigators on the iPrEx study, which included nearly 2,500 participants from the United States as well as Peru, Ecuador, Brazil, Thailand, and South Africa. The iPrEx study consented HIV- uninfected men who reported having sex with men as well as engaging in risky sexual behaviors. The study participants were randomized to either oral doses of a combination pill containing tenofovir (TDF) and emtricitabine (FTC) or a placebo pill. The results of this study indicated that subjects provided with preexposure antiviral treatments or "PrEp" had 44% reduction in HIV acquisition. Furthermore, the study showed that among those participants who took the drug at least 90% of the time, HIV acquisition was further reduced by 73%. Those who took the drug less than 90% of the time had a 21% reduction in HIV acquisition. Both the placebo pill and the PrEp groups showed similar rates of serious adverse events, suggesting that the use of FTC-TDF was well tolerated, although nausea was reported more frequently during the first four weeks of the PrEp group. These promising results suggest that combining PrEp with behavioral interventions has the potential to maximize the reduction of HIV incidence in MSM.

More About iPrEx       Link to Abstract       Fenway Institute Press Release