Many important biological determinants of HIV-1 disease progression and transmission map to the envelope glycoprotein, including antibody neutralization susceptibility, viral tropism for entry and epitopes for T cell response. Genetic and phenotypic characterizations of the envelope gene suggest a bottleneck effect in the spread of the virus to other body compartments and transmission, resulting in a predominantly homogenous viral population. However, the limitations in current methods to accurately assign HIV-1 coreceptor usage, distinguish genetic variations and detect minor variants in the HIV quasispecies within a patient and between transmission pairs have led to controversial findings. Furthermore, the small patient sample size studied has been too small to make broad generalization regarding mechanisms of HIV transmission and pathogensis. Lastly, these various properties of the envelope gene have been studied predominantly in subtype B infection and less clearly elucidated in HIV-1 subtype C, the most rapidly spreading and prevalent infection worldwide. We hypothesize that a heterogenous HIV-1 population with different envelope sequences and coreceptor usage are transmitted during infection but is not fully characterized and measured by our current available techniques. We propose to use novel and more sensitive methods to determine coreceptor usage and to perform in-depth sequencing and genetic analyses of the envelope gene from a large subtype C clinical cohort from Botswana. The envelope gene in subtype C infection will be studied in longitudinal samples, as well as between plasma-breast milk and mother-infant pairs. We plan to study in greater depth the properties of the HIV-1 subtype C envelope glycoprotein with the following specific aims: 1) identify clinical and genetic determinants of coreceptor switching, 2) assess for correlates of breastfeeding transmission of HIV-1 and 3) examine pattern of viral transmission among mother-to-child transmitting pairs occurring through different routes of MTCT using ultradeep sequencing. The results of this study will further the understanding of viral evolution in the context of transmission and disease progression, identify clinical correlates of transmission and disease progression, and ultimately give insights into potential strategies of prevention, treatment and vaccine development in those parts of the world most affected by HIV.
(provided by applicant): Understanding mechanisms of HIV pathogenesis, transmission and clinical progression will have public health relevance by guiding the design of HIV prevention and treatment strategies.
|Scully, Eileen; Lockhart, Ainsley; Huang, Lisa et al. (2016) Elevated Levels of Microbial Translocation Markers and CCL2 Among Older HIV-1-Infected Men. J Infect Dis 213:771-5|
|Henrich, Timothy J; Hu, Zixin; Li, Jonathan Z et al. (2013) Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis 207:1694-702|
|Wilkin, Timothy J; Lalama, Christina M; McKinnon, John et al. (2012) A pilot trial of adding maraviroc to suppressive antiretroviral therapy for suboptimal CD4âº T-cell recovery despite sustained virologic suppression: ACTG A5256. J Infect Dis 206:534-42|
|Lin, Nina H; Becerril, Carlos; Giguel, Francoise et al. (2012) Env sequence determinants in CXCR4-using human immunodeficiency virus type-1 subtype C. Virology 433:296-307|
|Lin, Nina H; Smeaton, Laura M; Giguel, FranÃ§oise et al. (2011) Prevalence and clinical associations of CXCR4-using HIV-1 among treatment-naive subtype C-infected women in Botswana. J Acquir Immune Defic Syndr 57:46-50|
|Henrich, Timothy J; Li, Jonathan Z; Felsenstein, Donna et al. (2010) Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions. J Infect Dis 202:1478-81|
|Lin, Nina H; Negusse, Daniel M; Beroukhim, Rameen et al. (2010) The design and validation of a novel phenotypic assay to determine HIV-1 coreceptor usage of clinical isolates. J Virol Methods 169:39-46|