Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa

Abstract

Objective:To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs).Design:Prospective cohort.Methods:Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3–6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-to-event endpoints: CD4+ cell count 350 cells/μl or less, viral load measurement at least 1 × 105 copies/ml, and clinical AIDS.Results:From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4+ hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09).Conclusion:Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials.

Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth

“…The discrepancy between van der Kerkhof et al and our study could reflect differences in the cohorts, experimental methods, Env sampling times, or time frame when neutralization breadth was measured. Furthermore, numerous biological distinctions have been reported in Env glycosylation, antigenicity, and immunogenicity, as well as in transmission and disease progression, based on HIV-1 subtype [6,9,36,46,64,68,73–80]. Indeed striking differences in conservation and variability of glycosylation sites are seen within and between HIV-1 subtypes [76,81,82].…”

“…ZEHRP and PSF are also part of the Rwanda Zambia HIV Research Group at Emory University (RZHRG; http://www.rzhrg.org). More recently Protocol C, a uniform vaccine-preparedness study developed and implemented by the International AIDS Vaccine Initiative (IAVI; http://www.iavi.org), was initiated and carried out at multiple sites in Africa, including ZEHRP and PSF [80]. …”

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

“…There is also evidence for reduced subtype C Gag-protease function relative to subtype B, corresponding with slower disease progression in subtype C-infected individuals; in Brazil, where subtype C cocirculates with subtypes B and F1 and intersubtype recombinants, subtype C was associated with higher CD4 counts (18). However, there are conflicting reports of the disease progression rate of subtype C relative to that of subtypes A and D (12,(15)(16)(17)59). Nevertheless, overall, our data suggest that the lower Gag-protease-driven replication capacity of subtypes A and C (in addition to the lower Pol-driven replication capacity for subtype A [35]) may contribute to slower disease progression in individuals infected with these subtypes.…”

Dynamics of viremia in primary HIV-1 infection in Africans: Insights from analyses of host and viral correlates

“…Recent assessment of disease progression (time to severe immunodeficiency) has revealed the role of African HIV-1 subtypes in pathogenesis (Amornkul et al, 2013). However, given the strong collinearity between geography and HIV-1 subtypes (Table 1), a more definitive elucidation of host and viral factors in HIV-1 pathogenesis in Africa may require the assembly of a genetically homogeneous cohort with diverse HIV-1 subtypes and adequate follow-up.…”