Abstract
Approximately 40% of HIV-1 infections occur in the female genital tract (FGT), primarily through heterosexual transmission. FGT factors determining outcome of HIV-1 exposure are incompletely understood, limiting prevention strategies. Here, humanized NOD-Rag1−/− γc−/− mice differentially reconstituted with human CD34+ -enriched hematopoietic stem cells (Hu-mice), were used to assess target cell frequency and viral inoculation dose as determinants of HIV-1 infection following intravaginal (IVAG) challenge. Results revealed a significant correlation between HIV-1 susceptibility and hCD45+ target cells in the blood, which correlated with presence of target cells in the FGT, in the absence of local inflammation. HIV-1 plasma load was associated with viral dose at inoculation and frequency of target cells. Events following IVAG HIV-1 infection; viral dissemination and CD4 depletion, were not affected by these parameters. Following IVAG inoculation, HIV-1 titres peaked, then declined in vaginal lavage while plasma showed a reciprocal pattern. The greatest frequency of HIV-1-infected (p24+) cells were found one week post-infection in the FGT versus blood and spleen, suggesting local viral amplification. Five weeks post-infection, HIV-1 disseminated into systemic tissues, in a dose-dependent manner, followed by depletion of hCD45+ CD3+ CD4+ cells. Results indicate target cell frequency in the Hu-mouse FGT is a key determinant of HIV-1 infection, which might provide a useful target for prophylaxis in women.
Highlights
Information regarding early transmission events in women is derived from a combination of epidemiological studies, mathematical modeling and experimental studies in non-human primate (NHP) and human tissue explants[8,9,10]
We showed that following IVAG inoculation with HIV-1 in humanized non-obese diabetic NOD-Rag1−/− γc−/− (NRG) mice reconstituted with human CD34+ enriched hematopoietic stem cells (Hu-mice), viral replication occurs locally, followed by the systemic dissemination and depletion of CD4+ target cells
Hu-mice reconstituted to varying levels of hCD45 (0.29–62.2%) were inoculated IVAG with either low dose (NL4.3-BAL 103 TCID50, N = 17) or high dose HIV-1 (105 TCID50, N = 17), and infection following viral challenge was determined by a positive HIV-1 viral titre in the plasma by 5 weeks post-viral exposure (Fig. 1)
Summary
Information regarding early transmission events in women is derived from a combination of epidemiological studies, mathematical modeling and experimental studies in non-human primate (NHP) and human tissue explants[8,9,10]. The epithelial barrier and infecting a small population of CD4+ target cells, a short period of local viral amplification is thought to be required prior to migration of the virus outside the FGT, at which point it can be detected in peripheral blood[8,12] This eclipse phase has been proposed to provide a window of opportunity to halt infection progression prior to the systemic spread of virus[8,9,13]. Studies have shown that within three to five weeks following infection HIV-1 establishes its characteristic reservoirs in the tissues (gut associated lymphoid tissue (GALT), spleen, liver, lung, brain, lymph nodes), indicating a productive systemic infection has occurred[8]. Our results demonstrate that the frequency of target cells supersedes viral dose at inoculation as the key determinant of successful HIV-1 infection in Hu-mice, even in the absence of local inflammation, and that the viral dose at inoculation determines subsequent viral titre in the plasma
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