Maraviroc Fails to Block SIV Infection in Orally Exposed Infant Macaques
Twice-daily oral maraviroc (Selzentry, Celsentri) failed to prevent SIVmac infection in infant macaques orally exposed to the virus. University of Pittsburgh researchers suggested their findings do not rule out potential use of oral maraviroc to protect human infants from maternal HIV because SIVmac can use multiple CCR5 receptors. The study was presented at AIDS 2016.
Thousands of human infants continue to become vertically infected with HIV worldwide, often during breastfeeding. Maraviroc, which thwarts HIV entry into T cells by blocking the CCR5 coreceptor, is a logical candidate for prophylaxis of mother-to-infant oral transmission of HIV. In phase-2 trials maraviroc proved an effective oral pre-exposure prophylaxis (PrEP) agent for high-risk women and men who have sex with men in the United States.
The macaque study involved nine animals six months in age, five treated orally with 300 mg/kg of maraviroc twice daily and four untreated. Macaques received maraviroc for two weeks before the first oral challenge with 10,000 TCID50 of SIVmac766XII. Challenges continued every two weeks through ongoing maraviroc treatment until all control animals became infected. SIVmac766XII combines a wild-type clone plus nine clones carrying two or three integrase mutations that do not affect the infectivity of the clone.
All treated macaques tolerated maraviroc well. Coreceptor occupancy analysis showed that maraviroc efficiently blocked CCR5 coreceptors on CD4 cells in the treated group. After the sixth SIVmac challenge, all four control macaques had become infected, as had three of five maraviroc-treated animals. The treated group did not differ from the control group in number of exposures needed to become infected. Maraviroc levels measured at times of expected peak and trough concentrations proved similar to therapeutic levels in HIV-infected maraviroc-treated people and never lay below limits of quantitation.
All infected macaques, whether treated with maraviroc or untreated, were similar in peak of acute viremia and development of chronic viremia. Maraviroc did significantly delay time to peak viremia. All treated and control macaques became infected with one SIVmac variant, a result suggesting that no animals were overexposed to virus in a way that might offset the antiviral effect of maraviroc. Levels of CD4-cell depletion were similar in the maraviroc-treated and untreated animals that became infected. Nor did the treated and control animals differ significantly in expression of CCR5 on CD4 cells or CD8 cells.
The University of Pittsburgh team concluded that blocking CCR5 with maraviroc "did not significantly impact SIV oral transmission." The researchers suggest, though, that results might differ in humans because SIVmac is "more promiscuous than HIV-1 with regard to coreceptor usage." That is, SIV can use alternative CCR5 coreceptors, such as BOB/GPR15 and Bonzo/STRL33. But the investigators also noted that previous studies using SHIV (an SIV virus with an HIV envelope) found that maraviroc did not block intrarectal transmission.