Frequency of Human CD45+ Target Cells is a Key Determinant of Intravaginal HIV-1 Infection in Humanized Mice

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.

Medroxyprogesterone acetate mediated alteration in the vaginal microbiota and microenvironment in a Kenyan sex worker cohort

“…Therefore, we decided to experimentally validate the main effects of DMPA on VMB diversity and vaginal glycogen. We recently optimized a humanized mouse model, reconstituted with human immune cells, that demonstrates HIV-1 infection following intravaginal challenge (33). We examined the effect of DMPA on diversity of the VMB in this model.…”

“…No studies have demonstrated a direct link between DMPA and enhanced susceptibility to HIV-1 in humanized mice. We thus experimentally assessed whether DMPA-treated humanized mice were more susceptible to HIV-1 in a heterosexual model of viral transmission (33) compared to untreated, control humanized mice. Humanized mice (control, no hormonal treatment, N=20) and DMPA-treated humanized mice (N=22) were challenged intravaginally with 10 5 TCID50/mL NL4.3-Bal-Env HIV-1 (33, 34).…”

“…We thus experimentally assessed whether DMPA-treated humanized mice were more susceptible to HIV-1 in a heterosexual model of viral transmission (33) compared to untreated, control humanized mice. Humanized mice (control, no hormonal treatment, N=20) and DMPA-treated humanized mice (N=22) were challenged intravaginally with 10 5 TCID50/mL NL4.3-Bal-Env HIV-1 (33, 34). HIV-1 viral load in peripheral blood was quantified by clinical RT-PCR 3-5 weeks following challenge (33).…”

“…Humanized mice (control, no hormonal treatment, N=20) and DMPA-treated humanized mice (N=22) were challenged intravaginally with 10 5 TCID50/mL NL4.3-Bal-Env HIV-1 (33, 34). HIV-1 viral load in peripheral blood was quantified by clinical RT-PCR 3-5 weeks following challenge (33). The proportion of infected DMPA-treated humanized mice was 17/22 (77%), which was significantly higher (P=0.014) than those not receiving DMPA (7/20, 35%) (Figure 6).…”

“…Experimental protocols were approved by HiREB and McMaster University Animal Research Ethics Board (AREB), AUP# 14-09-40, in accordance with Canadian Council of Animal Care guidelines. Humanized NRG mice were generated as described (33). Briefly, 4 day-old mice were irradiated and injected with CD34-enriched placental cord blood stem cells, and left for 12 weeks to allow human immune reconstitution of bone marrow and peripheral tissues.…”