Low-dose penile SIVmac251 exposure of rhesus macaques infected with adenovirus type 5 (Ad5) and then immunized with a replication-defective Ad5-based SIV gag/pol/nef vaccine recapitulates the results of the phase IIb step trial of a similar HIV-1 vaccine.

The Step Trial showed that the MRKAd5 HIV-1 subtype B Gag/Pol/Nef vaccine did not protect men from HIV infection or reduce setpoint plasma viral RNA (vRNA) levels but, unexpectedly, it did modestly enhance susceptibility to HIV infection in adenovirus type 5 (Ad5)-seropositive, uncircumcised men. As part of the process to understand the results of the Step Trial, we designed a study to determine whether rhesus macaques chronically infected with a host-range mutant Ad5 (Ad5hr) and then immunized with a replication defective Ad5 SIVmac239 Gag/Pol/Nef vaccine were more resistant or susceptible to SIV infection than unimmunized rhesus macaques challenged with a series of escalating dose penile exposures to SIVmac 251. The Ad5 SIV vaccine induced CD8(+) T cell responses in 70% of the monkeys, which is similar to the proportion of humans that responded to the vaccine in the Step Trial. However, the vaccine did not protect vaccinated animals from penile SIV challenge. At the lowest SIV exposure dose (10(3) 50% tissue culture infective doses), 2 of 9 Ad5-seropositive animals immunized with the Ad5 SIV vaccine became infected compared to 0 of 34 animals infected in the other animal groups (naive animals, Ad5-seropositive animals immunized with the empty Ad5 vector, Ad5-seronegative animals immunized with the Ad5 SIV vaccine, and Ad5-seronegative animals immunized with the empty Ad5 vector). Penile exposure to more concentrated virus inocula produced similar rates of infection in all animal groups. Although setpoint viral loads were unaffected in Step vaccinees, the Ad5 SIV-immunized animals had significantly lower acute-phase plasma vRNA levels compared to unimmunized animals. Thus, the results of the nonhuman primate (NHP) study described here recapitulate the lack of protection against HIV acquisition seen in the Step Trial and suggest a greater risk of infection in the Ad5-seropositive animals immunized with the Ad5 SIV vaccine. Further studies are necessary to confirm the enhancement of virus acquisition and to discern associated mechanisms.

SIVmac251 is inefficiently transmitted to rhesus macaques by penile inoculation with a single SIVenv variant found in ramp-up phase plasma.

Abstract Despite the fact that approximately half of all HIV patients acquire infection through penile exposure, there have been no recent studies of penile SIV transmission in rhesus macaques and the nature of the virus variants transmitted, target cells, and pathways of virus dissemination to systemic lymphoid tissues are not known. Single genome amplification (SGA) and sequencing of HIV-1 RNA in plasma of acutely infected humans allows the identification and enumeration of transmitted/founder viruses responsible for productive systemic infection. Studies using the SGA strategy have shown that intrarectal and intravaginal SIV transmission to macaques recapitulates key features of human HIV transmission. To date, no studies have used the SGA assay to identify transmitted/founder virus(es) in macaques infected after penile SIV exposure. Here we report that SIV can be transmitted by penile SIV exposure. However, similar exposure to a high-dose inoculum infects only about half the animals, which is about 50% less efficient transmission than occurs after vaginal SIV challenge. In addition, only a single SIV env variant established the systemic infection in all five animals that became infected after penile exposure, a result that is consistent with low incidence and few transmitted HIV variants in heterosexually infected men. Our results suggest that the penile transmission of SIVmac251 in rhesus macaques recapitulates the key features of penile HIV-1 transmission and may provide insight into host or viral factors that permit penile transmission and dissemination. Furthermore, this SIV challenge exposure route will be useful in testing vaccines and other prophylactic approaches.