HIV-1 fitness is a complex parameter defined by the adaptability of the virus to a given environment. Over the past four years we have studied the ex vivo fitness of HIV-1 in various primary human cells and have explored possible relationships with disease progression as well as global and temporal evolution of the virus in the human epidemic. In this proposal we will focus on changes in replicative HIV-1 fitness during the natural history of disease and following discrete transmission events in subtype A, C, and D infected patients. Over the past three years, we have analyzed samples from over 266 Zimbabwean and Ugandan women recruited within three months of acute infections and have followed their progression every three months thereafter. This cohort also provides an excellent opportunity to compare the affects of HIV-1 subtype on infection and subsequent disease outcomes. As a lead up to this study, we have published fairly exhaustive comparisons on the fitness of HIV types (1 or 2), groups (M and O), subtype (A through F), and recombinant forms and found the order of ex vivo HIV replicative fitness to be: HIV-1 group M (subtypes A, B, D, F, CRF01_AE, CRF02_AG, CRF012_BF) >subtype C >HIV-2 """""""" HIV-1 group O. Based on preliminary data that shows slower disease progression in subtype C infections and that subtype C virus is intrinsically less fit, our study will address if these two observations are linked and if subtype C represents an attenuated HIV-1 form. These hypotheses will be tested in the following specific aims.
Specific aim 1 : To establish a rapid yeast-based env cloning system to produce chimeric env viruses. To further examine if ex vivo HIV-1 fitness maps to the env gene and is controlled by the HIV-1 entry process into host cells.
Specific aim 2 : To explore the relationships between HIV-1 fitness/diversity at acute/early infection Specific aim 3: To examine changes in viral fitness, genetic diversity, and other clinical correlates during disease progression. To relate changes to subtype.
|Pankrac, Joshua; Klein, Katja; McKay, Paul F et al. (2018) A heterogeneous human immunodeficiency virus-like particle (VLP) formulation produced by a novel vector system. NPJ Vaccines 3:2|
|Klein, Katja; Nickel, Gabrielle; Nankya, Immaculate et al. (2018) Higher sequence diversity in the vaginal tract than in blood at early HIV-1 infection. PLoS Pathog 14:e1006754|
|Bagaya, Bernard S; Tian, Meijuan; Nickel, Gabrielle C et al. (2017) An in vitro Model to Mimic Selection of Replication-Competent HIV-1 Intersubtype Recombination in Dual or Superinfected Patients. J Mol Biol 429:2246-2264|
|Gibson, Richard M; Nickel, Gabrielle; Crawford, Michael et al. (2017) Sensitive detection of HIV-1 resistance to Zidovudine and impact on treatment outcomes in low- to middle-income countries. Infect Dis Poverty 6:163|
|Asmal, Mohammed; Lane, Sophie; Tian, Meijuan et al. (2016) Pathogenic infection of Rhesus macaques by an evolving SIV-HIV derived from CCR5-using envelope genes of acute HIV-1 infections. Virology 499:298-312|
|Choi, Eunsil; Michalski, Chad J; Choo, Seung Ho et al. (2016) First Phase I human clinical trial of a killed whole-HIV-1 vaccine: demonstration of its safety and enhancement of anti-HIV antibody responses. Retrovirology 13:82|
|Tebit, Denis M; Patel, Hamish; Ratcliff, Annette et al. (2016) HIV-1 Group O Genotypes and Phenotypes: Relationship to Fitness and Susceptibility to Antiretroviral Drugs. AIDS Res Hum Retroviruses 32:676-88|
|Johnson, Aaron L; Dirk, Brennan S; Coutu, Mathieu et al. (2016) A Highly Conserved Residue in HIV-1 Nef Alpha Helix 2 Modulates Protein Expression. mSphere 1:|
|Krebs, Kendall C; Tian, Meijuan; Asmal, Mohammed et al. (2016) Infection of rhesus macaques with a pool of simian immunodeficiency virus with the envelope genes from acute HIV-1 infections. AIDS Res Ther 13:41|
|Venner, Colin M; Nankya, Immaculate; Kyeyune, Fred et al. (2016) Infecting HIV-1 Subtype Predicts Disease Progression in Women of Sub-Saharan Africa. EBioMedicine 13:305-314|
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