Pathogenic Consequences of Vaginal Infection with CCR5-Tropic Simian-Human Immunodeficiency Virus SHIV _SF162P3N

Abstract

We previously reported efficient transmission of the pathogenic R5 simian-human immunodeficiency virus SHIV SF162P3N isolate in Indian rhesus macaques by intravenous and intrarectal inoculations, with a switch to CXCR4 coreceptor usage in ∼50% of infected animals that progressed rapidly to disease. Since women continue to be disproportionately affected by HIV, we developed an animal model based on the intravaginal challenge of female rhesus monkeys with SHIV SF162P3N and sought to validate the utility of this model to study relevant aspects of HIV transmission and pathogenesis. The effect of viral dose on infection outcome was evaluated to determine the optimal conditions for the evaluation of HIV-1 preventive and therapeutic strategies. We found that the virus can successfully cross the vaginal mucosal surface to establish infection and induce disease with coreceptor switch, but with lower efficiencies compared to intravenous and rectal transmissions. In contrast to intrarectal infection, peak and cumulative viral load over a 1 year-infection period were significantly greater in macaques exposed intravaginally to lower rather than higher inoculum doses. Moreover, low and transient viremia was observed only in macaques that were challenged intravaginally twice within the same day with a high dose of virus, which can be seen as doubling the dose. Taken together, these results show that SHIV SF162P3N can successfully transmit across the genital mucosa, undergo coreceptor switch, and induce disease. However, the administered dose appears to impact SHIV SF162P3N vaginal infection outcome in an unexpected manner.

Development of Broadly Neutralizing Antibodies and Their Mapping by Monomeric gp120 in Human Immunodeficiency Virus Type 1-Infected Humans and Simian-Human Immunodeficiency Virus SHIV SF162P3N -Infected Macaques

“…Previously, we infected Indian and Chinese rhesus macaques with a singledose intrarectal challenge of pathogenic uncloned SHIV SF162P3N (10)(11)(12)(13) or its derivative molecular clones (14). We identified 13 animals with sustained viral loads for at least a year, including two Chinese rhesus macaques, GL26 and GB40 (12).…”

“…The rhesus plasma and PBMC samples analyzed in this study were from macaques described in previous studies that had been inoculated with the pathogenic clade B R5 SHIV SF162P3N (10)(11)(12)(13)(14) as an uncloned viral swarm or with its derivative molecular clones. All of the rhesus specimens were collected at the Tulane National Primate Research Center in compliance with its Guide for Care and Use of Laboratory Animals and under protocols approved by the Institutional Animal Care and Use Committee (IACUC).…”

“…Instead, 7 macaques in the latter study exhibited cross-reactive antibodies with limited potency, and one animal, CL5E, displayed impressive neutral-ization breadth and potency (6). Here, we screened 13 viremic macaques infected with the clade B R5 uncloned SHIV SF162P3N (10)(11)(12)(13) or its derivative molecular clones (14) for neutralizing activity against HIV-1. Compared with the commonly used SHIV SF162P3 , the lineage-related late isolate SHIV SF162P3N is more macaque adapted and more pathogenic (10), and macaques infected with the virus are more likely to demonstrate a sustained viral load (13).…”

“…Here, we screened 13 viremic macaques infected with the clade B R5 uncloned SHIV SF162P3N (10)(11)(12)(13) or its derivative molecular clones (14) for neutralizing activity against HIV-1. Compared with the commonly used SHIV SF162P3 , the lineage-related late isolate SHIV SF162P3N is more macaque adapted and more pathogenic (10), and macaques infected with the virus are more likely to demonstrate a sustained viral load (13). Since high levels of plasma viral load have been associated with bnAb development in HIV-1-infected individuals (15), these viremic SHIV SF162P3N -infected animals are of interest to screen for possible bnAbs against HIV-1.…”

Generation of Lineage-Related, Mucosally Transmissible Subtype C R5 Simian-Human Immunodeficiency Viruses Capable of AIDS Development, Induction of Neurological Disease, and Coreceptor Switching in Rhesus Macaques

“…Notably, neutralizing antibodies against the homologous SHIVC109F.PB4 molecular clone could be detected in GC87 (dilution of plasma inhibiting infection by 50% [ID 50 titer], 1:1,000) but not in EL78 (ID 50 titer, Ͻ1:20) at the time of virus isolation. Furthermore, because variants with increased pathogenicity and replication fitness have been identified late in infection in HIV-1-infected individuals as well as in SIV/SHIV-infected macaques that progressed to disease while maintaining an exclusively R5 tropic virus population (42,44,45), we also recovered viruses from the plasma of EL78 at the time of necropsy (designated SHIVC109P3N) for comparative studies with the early lineagerelated virus SHIVC109P3. Infection of rhPBMCs with the three viruses was blocked by the CCR5 antagonist TAK779 but not by the CXCR4 inhibitor AMD3100, showing that these viruses maintained CCR5 specificity (Fig.…”