Doctor of Philosophy
Microbiology and Immunology
Arts, Eric J.
Human immunodeficiency virus type 1 (HIV-1) emerged in the human population shortly after the turn of the 19th century. Distribution of HIV-1 across the globe over the past 30–35 years can be traced to founder events with primordial HIV strains from sub-Saharan Africa. Even considering the burden of HIV in Africa, our knowledge of HIV-1 disease is still largely limited to subtype B HIV-1, a strain responsible for 3 million infections in North America and Europe as compared to the 33 million that are infected with HIV-1 subtypes A, C, D, and circulating and unique recombinant forms.
This dissertation analyzes data and archived samples from a cohort of HIV+ women in Uganda and Zimbabwe to assess the role of HIV-1 Group M subtype in disease progression, viral replicative fitness and cellular entry efficiency. Generalized estimating equation models are employed to calculate average rates of CD4+ T-cell loss over the course of disease, investigate circulating viral load, and compare depletion of memory T-cell subsets in CD4+ and CD8+ T-cells. Fluorescent tissue culture assays of HIV-1 entry were used to phenotypically evaluate entry efficiency and its association with replicative fitness.
Ugandan and Zimbabwean women infected with HIV-1 subtype C had 2.5-fold slower rates of CD4 T-cell declines and higher frequencies of long-term non-progression than those infected with subtype A or D, a difference not associated with any other clinical parameters. Relative replicative fitness and entry efficiency of HIV-1 variants directly correlated with virulence in the patients, subtype D > A > C. These relationships were maintained in both assays evaluating HIV-induced cell-fusion rates, viral particle entry rates and CD4 receptor affinity.
The primary burden of HIV infection is placed on T-cell memory populations that are focal points for progeny virion production, the latent proviral reservoir, and immune activation. All subtypes depleted effector memory T-cells preferentially, however subtype D infections lost these cells at about twice the rate of subtype C infections. Finally, subtype D was found to uniquely deplete CD8+ memory T-cells.
Venner, Colin M., "HIV-1 Group M Subtype Fitness, Disease Progression, and Entry Efficiency" (2019). Electronic Thesis and Dissertation Repository. 6179.
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