Thesis Format

Integrated Article

HIV-1 Group M Subtype Fitness, Disease Progression, and Entry Efficiency

Colin M. Venner, The University of Western OntarioFollow

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Arts, Eric J.

Abstract

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.

Recommended Citation

Venner, Colin M., "HIV-1 Group M Subtype Fitness, Disease Progression, and Entry Efficiency" (2019). Electronic Thesis and Dissertation Repository. 6179.
https://ir.lib.uwo.ca/etd/6179