Low-Dose Mucosal Simian Immunodeficiency Virus Infection Restricts Early Replication Kinetics and Transmitted Virus Variants in Rhesus Monkeys

Abstract

Defining the earliest virologic events following human immunodeficiency virus type 1 (HIV-1) transmission may be critical for the design of vaccine strategies aimed at blocking acquisition of HIV-1 infection. In particular, the length of the eclipse phase and the number of transmitted virus variants may define the window in which a prophylactic vaccine must act. Here we show that the dose of the virus inoculum affects these key virologic parameters following intrarectal simian immunodeficiency virus (SIV) infection of rhesus monkeys. Low-dose SIV infection resulted in a lengthened eclipse phase, fewer transmitted virus variants, and decreased innate immune activation compared with these parameters in high-dose SIV infection. These data suggest a mechanism by which it may be considerably easier for a vaccine to protect against low-risk HIV-1 transmission than against high-risk HIV-1 transmission. These findings have implications for the design and interpretation of HIV-1 vaccine efficacy studies.

Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody

“…Compiling all of the changes from each identified founder sequence, we found that 54% of all sequences were identical to their own consensus sequence, 35% had one change, 10% had two changes, and only 1% had three changes. This distribution and the overall homogeneity within each phylogenetically distinct lineage are consistent with the short duration of infection, and with previous reports of maximum diversity during acute infection following mucosal transmission (20,21,23). Most SHIV-162P3 and SHIV-162P4 infections were established in control animals by either a single, or less often two, founder viruses (Fig.…”

“…The median number of founder viruses in DEN3 and HEC gel recipients, combined, was 1, irrespective of the challenge virus (mean ± SEM, 1.6 ± 0.34). Thus, even though progesterone was used to thin the vaginal epithelium and facilitate transmission, the number of founder viruses is similar to those seen in sexually infected humans or in macaques challenged mucosally in the absence of progesterone (20,21,23).…”

“…We used plasma samples from the various SHIV-162P3 and SHIV-16P4-infected animals described above to quantify the number of viral lineages that expanded in each of them (Fig. 4) (20,21). Four additional animals that became infected with SHIV-162P3 after receiving a DC-SIGN-Fc fusion protein vaginally before challenge were also included in the analysis.…”

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

“…Importantly, the features of HIV-1 transmission and early diversification are mirrored in SIV-infected macaques. SGA analysis of swarm challenge stocks SIVmac251 or SIVsmE660, and isolated virus soon after intra-rectal or intravaginal inoculation of macaques have demonstrated the presence of low diversity env sequence lineages that share a high level of genetic identity to the env spectrum in the challenge stock [53,106,107]. Indeed, it was found that a limited number of transmitted variants (1-10 species) establish infection, thus offering strong support for and confirmation of the observed patterns of HIV-1 transmission.…”

“…Consistent rectal infection can be achieved in rhesus macaques within the first four exposures with an inoculum of 10 5 RNA copies of SHIV162p3 which is within the range of HIV-1 RNA levels in semen (10 3 -10 6 copies/ml). It was demonstrated that low-dose SIV infection of rhesus macaques, unlike high dose, gave rise to a longer eclipse phase (the time period between infection and first appearance of systemic viremia), and lowered activation of innate immunity [106]. No association of adaptive immune T-cell responses upon repeated rectal exposures and inherent resistance or delayed susceptibility to infection with SHIV162P3 among some rhesus macaques validates the use of this model as an effective approach to test various HIV prevention strategies .…”