Relative Transmissibility of an R5 Clade C Simian‐Human Immunodeficiency Virus Across Different Mucosae in Macaques Parallels the Relative Risks of Sexual HIV‐1 Transmission in Humans via Different Routes

African green monkeys (AGMs) are naturally infected with a simian immunodeficiency virus (SIVagm) that is nonpathogenic in its host. Although SIVagm is common and widespread, little is known about the mechanisms that govern its transmission. Since the earliest virus-host interactions may provide key insights into the nonpathogenic phenotype of SIVagm, we developed a mucosal transmission model for this virus. Using plasma from an acutely infected AGM as the virus inoculum, we exposed adult and juvenile AGMs, as well as pigtailed macaques (PTMs)

Section: Discussionmentioning

confidence: 97%

Mucosal Simian Immunodeficiency Virus Transmission in African Green Monkeys: Susceptibility to Infection Is Proportional to Target Cell Availability at Mucosal Sites

Pandrea

Parrish

Raehtz

et al. 2012

“…The SHIV-1157i stock was generated using a rapid animal-to-animal adaptation strategy by transferring virus at peak viremia from one animal to the next, and mucosal transmissibility and pathogenicity was demonstrated after five serial passages with SHIV-1157ip (28) and with the late-stage virus SHIV-1157ipd3N4. Compared to the original infectious SHIV1157i clone, mutations in the passaged viruses were present in variable loops resulting in decreased 2G12 sensitivity, and a 33-amino-acid insertion was observed in gp41 (29). Similarly, although the SHIV-C109F.PB4 clone was infectious, the mucosal transmissibility was demonstrated with the in vivo passaged viruses SHIV-C109P3, SHIV-C109P4, and SHIV-C109P3N, which contained amino acid changes in the variable loops and potential N-linked glycosylation sites (14).…”

Section: Discussionmentioning

confidence: 98%

Generation and Evaluation of Clade C Simian-Human Immunodeficiency Virus Challenge Stocks

Chang

Tartaglia

Whitney

et al. 2015

The development of a panel of mucosally transmissible simian-human immunodeficiency virus (SHIV) challenge stocks from multiple virus clades would facilitate preclinical evaluation of candidate HIV-1 vaccines and therapeutics. The majority of SHIV stocks that have been generated to date have been derived from clade B HIV-1 env sequences from viruses isolated during chronic infection and typically required serial animal-to-animal adaptation for establishing mucosal transmissibility and pathogenicity. To capture essential features of mucosal transmission of clade C viruses, we produced a series of SHIVs with early clade C HIV-1 env sequences from acutely HIV-1-infected individuals from South Africa. SHIV-327c and SHIV-327cRM expressed env sequences that were 99.7 to 100% identical to the original HIV-1 isolate and did not require in vivo passaging for mucosal infectivity. These challenge stocks infected rhesus monkeys efficiently by both intrarectal and intravaginal routes, replicated to high levels during acute infection, and established chronic setpoint viremia in 13 of 17 (76%) infected animals. The SHIV-327cRM challenge stock was also titrated for both single, highdose intrarectal challenges and repetitive, low-dose intrarectal challenges in rhesus monkeys. These SHIV challenge stocks should facilitate the preclinical evaluation of vaccines and other interventions aimed at preventing clade C HIV-1 infection. IMPORTANCEWe describe the development of two related clade C SHIV challenge stocks. These challenge stocks should prove useful for preclinical testing of vaccines and other interventions aimed at preventing clade C HIV-1 infection.

“…or i.r., but that this rate was lower after inoculation by the i.v.g. route (6,8,14,38,42,54). Moreover, the kinetics of virus dissemination was slower, and the RNA levels were more variable in monkeys infected by the i.v.g.…”

Section: Discussionmentioning

confidence: 99%

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

Shakirzyanova

Tsai

Ren

et al. 2012

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.