Doherty Institute - Research Publications
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ItemNo Preview AvailableRegional Analysis of Intact and Defective HIV Proviruses in the Brain of Viremic and Virally Suppressed People with HIV(WILEY, 2023-10)Here, we provide the first regional analysis of intact and defective HIV reservoirs within the brain. Brain tissue from both viremic and virally suppressed people with HIV (PWH) harbored HIV pol DNA in all regions tested, with lower levels present in basal ganglia and cerebellum relative to frontal white matter. Intact proviruses were primarily found in the frontal white matter but also detected in other brain regions of PWH, demonstrating frontal white matter as a major brain reservoir of intact, potentially replication competent HIV DNA that persists despite antiretroviral therapy. ANN NEUROL 2023;94:798-802.
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ItemUnderstanding the mechanisms driving the spread of subtype C HIV-1(ELSEVIER, 2020-03)Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is the most prevalent form of HIV-1 globally, accounting for approximately 50% of infections worldwide. C-HIV is the predominant and near-exclusive subtype in the low resource regions of India and Southern Africa. Given the vast diversity of HIV-1 subtypes, it is curious as to why C-HIV constitutes such a large proportion of global infections. This enriched prevalence may be due to phenotypic differences between C-HIV isolates and other viral strains that permit enhanced transmission efficiency or, pathogenicity, or might due to the socio-demographics of the regions where C-HIV is endemic. Here, we compare the mechanisms of C-HIV pathogenesis to less prominent HIV-1 subtypes, including viral genetic and phenotypic characteristics, and host genetic variability, to understand whether evolutionary factors drove C-HIV to predominance.
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ItemLongitudinal analysis of subtype C envelope tropism for memory CD4+T cell subsets over the first 3 years of untreated HIV-1 infection(BMC, 2020-08-06)BACKGROUND: HIV-1 infects a wide range of CD4+ T cells with different phenotypic properties and differing expression levels of entry coreceptors. We sought to determine the viral tropism of subtype C (C-HIV) Envelope (Env) clones for different CD4+ T cell subsets and whether tropism changes during acute to chronic disease progression. HIV-1 envs were amplified from the plasma of five C-HIV infected women from three untreated time points; less than 2 months, 1-year and 3-years post-infection. Pseudoviruses were generated from Env clones, phenotyped for coreceptor usage and CD4+ T cell subset tropism was measured by flow cytometry. RESULTS: A total of 50 C-HIV envs were cloned and screened for functionality in pseudovirus infection assays. Phylogenetic and variable region characteristic analysis demonstrated evolution in envs between time points. We found 45 pseudoviruses were functional and all used CCR5 to mediate entry into NP2/CD4/CCR5 cells. In vitro infection assays showed transitional memory (TM) and effector memory (EM) CD4+ T cells were more frequently infected (median: 46% and 25% of total infected CD4+ T cells respectively) than naïve, stem cell memory, central memory and terminally differentiated cells. This was not due to these subsets contributing a higher proportion of the CD4+ T cell pool, rather these subsets were more susceptible to infection (median: 5.38% EM and 2.15% TM cells infected), consistent with heightened CCR5 expression on EM and TM cells. No inter- or intra-participant changes in CD4+ T cell subset tropism were observed across the three-time points. CONCLUSIONS: CD4+ T cell subsets that express more CCR5 were more susceptible to infection with C-HIV Envs, suggesting that these may be the major cellular targets during the first 3 years of infection. Moreover, we found that viral tropism for different CD4+ T cell subsets in vitro did not change between Envs cloned from acute to chronic disease stages. Finally, central memory, naïve and stem cell memory CD4+ T cell subsets were susceptible to infection, albeit inefficiently by Envs from all time-points, suggesting that direct infection of these cells may help establish the latent reservoir early in infection.