In a previous report from the AIDS 2018 conference in Amsterdam, I briefly covered a presentation by Sarah Joseph from the University of North Carolina suggesting that the bulk of the persistent, replication-competent HIV reservoir is formed around the time that antiretroviral therapy (ART) is initiated. Details of the study have now been published in Science Translational Medicine, and Joseph and colleagues have also outlined how the findings might be exploited therapeutically in a separate open access paper in Frontiers in Immunology.
The main study analyzed nine women participating in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 cohort in KwaZulu-Natal. The women were enrolled during primary HIV infection, but did not begin ART until reaching the CD4 thresholds specified in contemporaneous South African treatment guidelines (which shifted from <200 to <350 during follow up).
The researchers performed quantitative virus outgrowth assays (QVOA) on blood samples taken from participants after an average of five years on ART (the QVOA measures the size of the replication-competent HIV reservoir present in the sample). The researchers then genetically sequenced the HIV that was detected by the QVOA and compared the results with viral sequences detected during the period prior to ART initiation, when samples were taken every six months on average.
The comparison of pre-ART HIV sequences with those subsequently detected by QVOA demonstrated that, in most cases, viruses had entered the reservoir during the year before ART was started. In four of the women, more than 90% of the HIV identified in the QVOA entered the reservoir in the year preceding ART. The median value for all nine was 78%. HIV sequences that were present within the first year of infection represented only 4% of viruses in the post-ART reservoir.
There were two exceptions to this general picture: in one case, the replication-competent HIV reservoir was mostly comprised of viruses from the early to middle period of untreated infection. In the second case, it appeared that viruses had seeded the reservoir continually prior to treatment, but there was a bias toward variants present during the year before ART was begun.
The results echo a previously published study by Johanna Brodin and colleagues, which found that ~60% of the HIV DNA sequences detectable after ART initiation were most closely related to HIV RNA variants present in blood samples just before treatment was started. Notably, the population in this study was quite different, mainly comprising Swedish men with clade B HIV infection.
The researchers suggest that during untreated HIV infection, virus-infected cells are typically in an activated, short-lived state that largely precludes the generation of long-lived cells containing latent HIV. When ART suppresses viral load, some virus-infected cells are able to transition into a long-lived resting memory state with HIV integrated into their genomes, thus establishing the latent reservoir. In the authors’ words: “These findings suggest that profound immunologic changes at the time of ART may allow HIV-infected cells to become long-lived memory cells and form most of the stable reservoir.”
This suggestion is broadly consistent with what has been learned about the generation of memory T cells from basic science research – when the level of an antigen is high, memory cell formation is limited, but when antigen levels decline a population of long-lived antigen-specific memory cells develops (a process called memory T cell differentiation or maturation).
In Frontiers in Immunology, Joseph and colleagues discuss the therapeutic implications of their results, writing: “Strategies to limit the formation of the stable HIV-1 reservoir could be combined with ART initiation, when patients are receiving intense clinical care. Preventing generation of long-lived latently infected CD4+ T cells should result in a smaller HIV-1 reservoir, providing a less intractable target for curative approaches. Reducing the size of the HIV-1 reservoir may also reduce ongoing immune senescence and HIV-1 co-morbidities experienced by PLWH on ART.”
The specific approach they have in mind is the short-term use of antibodies against the cell surface molecule CD127. These antibodies block interactions between the cytokine interleukin-7 (IL-7) and its cellular receptor, and these interactions are crucial in the formation of memory CD4 T cells. Several anti-CD127 antibodies are already in clinical trials as potential treatments for autoimmune and inflammatory conditions. Studies in people with HIV initiating ART are likely to be in the works.
Comments