Early Postinfection Antiviral Treatment Reduces Viral Load and Prevents CD4⁺Cell Decline in HIV Type 2-Infected Macaques

Abstract

Reports of significant reductions in plasma viral load by anti-HIV drugs have raised the possibility that antiviral therapy, if initiated sufficiently early, may result in sustained control of infection and prolonged clinical benefits. We evaluated the effects of intervention coincident with infection using an antiviral nucleoside, d4T, in Macaca nemestrina infected with a highly pathogenic isolate of HIV-2 (HIV-2[287]). Infection with this virus reproducibly results in high viremia and rapid CD4+ cell depletion, allowing a sensitive measurement of the treatment effect on viral load and clinical outcome. Compared to the control group, d4T-treated macaques showed significantly lower (2-3 log10) plasma- and cell-associated viral load. No CD4+ cell decline was observed in the treatment group while on therapy with d4T whereas CD4+ cells of control macaques declined from a preinfection mean of 32% of PBMCs to below 10%. Notably, when d4T treatment was withdrawn after 16 weeks, five of the six macaques continued to control viral load and have maintained normal CD4+ cell level for more than a year. These results demonstrate that early antiviral intervention, even of a limited duration, may constitute an important strategy against lentiviral-induced disease.

Passive Immunotherapy in Simian Immunodeficiency Virus-Infected Macaques Accelerates the Development of Neutralizing Antibodies

“…Animals were treated at the time of viral exposure and for 16 weeks, followed by cessation of treatment. Five of six d4T-treated macaques and none of six controls controlled the virus and maintained normal CD4 ϩ cell counts for 1 year (52). Similar benefits accrued with PMPA [(R)-9-(2-phosphonylmethoxypropyl)adenine] treatment of SIV-exposed macaques, where timing of administration affected the efficacy (47,48).…”

Containment of Simian Immunodeficiency Virus Infection: Cellular Immune Responses and Protection from Rechallenge following Transient Postinoculation Antiretroviral Treatment

“…In particular, the potential contribution of immune mechanisms has not been addressed, nor has the possibility that animals protected from establishment of persistent infection by postinoculation antiretroviral treatment may be protected from subsequent rechallenge, although these issues have been explored in murine retroviral models (20,(35)(36)(37)(38). Similarly, previous studies have suggested but not definitively demonstrated the ability of postinoculation treatment to produce a beneficial downmodulation of viral replication, following withdrawal of drug treatment, even if the establishment of persistent infection is not prevented (43,48,52).…”

Use of Animal Models for Anti-HIV Drug Development

“…Unfortunately, PMEA was very toxic in vivo, which lead to the development of the related and less-toxic compound tenofovir (previously called PMPA), which has been studied extensively in monkeys for viral inhibition (Balzarini et al, 1991;Lifson et al, 2003;Smith et al, 2000a;Tsai et al, 1998). Another RT inhibitor, stavudine, was tested for antiretroviral properties in HIV-2-infected macaques (Watson et al, 1997). And after many years of screening compounds in vitro, a precursor to the first FDA-approved integrase inhibitor, raltegravir, was shown to be effective in viral inhibition in the macaque model (Hazuda et al, 2004).…”