Preclinical Assessment of HIV Vaccines and Microbicides by Repeated Low-Dose Virus Challenges

BACKGROUND: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against “real life” exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. METHODS AND FINDINGS: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. CONCLUSION: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions

Evolution of the uniquely adaptable lentiviral envelope in a natural reservoir host

BACKGROUND: The ability of emerging pathogens to infect new species is likely related to the diversity of pathogen variants present in existing reservoirs and their degree of genomic plasticity, which determines their ability to adapt to new environments. Certain simian immunodeficiency viruses (SIVcpz, SIVsm) have demonstrated tremendous success in infecting new species, including humans, resulting in the HIV-1 and HIV-2 epidemics. Although SIV diversification has been studied on a population level, the essential substrates for cross-species transmission, namely SIV sequence diversity and the types and extent of viral diversification present in individual reservoir animals have not been elucidated. To characterize this intra-host SIV diversity, we performed sequence analyses of clonal viral envelope (env) V1V2 and gag p27 variants present in individual SIVsm-infected sooty mangabeys over time. RESULTS: SIVsm demonstrated extensive intra-animal V1V2 length variation and amino acid diversity (le38%), and continual variation in V1V2 N-linked glycosylation consensus sequence frequency and location. Positive selection was the predominant evolutionary force. Temporal sequence shifts suggested continual selection, likely due to evolving antibody responses. In contrast, gag p27 was predominantly under purifying selection. SIVsm V1V2 sequence diversification is at least as great as that in HIV-1 infected humans, indicating that extensive viral diversification in and of itself does not inevitably lead to AIDS. CONCLUSION: Positive diversifying selection in this natural reservoir host is the engine that has driven the evolution of the uniquely adaptable SIV/HIV envelope protein. These studies emphasize the importance of retroviral diversification within individual host reservoir animals as a critical substrate in facilitating cross-species transmission

SIVsm Quasispecies Adaptation to a New Simian Host

Despite the potential for infectious agents harbored by other species to become emerging human pathogens, little is known about why some agents establish successful cross-species transmission, while others do not. The simian immunodeficiency viruses (SIVs), certain variants of which gave rise to the human HIV-1 and HIV-2 epidemics, have demonstrated tremendous success in infecting new host species, both simian and human. SIVsm from sooty mangabeys appears to have infected humans on several occasions, and was readily transmitted to nonnatural Asian macaque species, providing animal models of AIDS. Here we describe the first in-depth analysis of the tremendous SIVsm quasispecies sequence variation harbored by individual sooty mangabeys, and how this diverse quasispecies adapts to two different host species—new nonnatural rhesus macaque hosts and natural sooty mangabey hosts. Viral adaptation to rhesus macaques was associated with the immediate amplification of a phylogenetically related subset of envelope (env) variants. These variants contained a shorter variable region 1 loop and lacked two specific glycosylation sites, which may be selected for during acute infection. In contrast, transfer of SIVsm to its natural host did not subject the quasispecies to any significant selective pressures or bottleneck. After 100 d postinfection, variants more closely representative of the source inoculum reemerged in the macaques. This study describes an approach for elucidating how pathogens adapt to new host species, and highlights the particular importance of SIVsm env diversity in enabling cross-species transmission. The replicative advantage of a subset of SIVsm variants in macaques may be related to features of target cells or receptors that are specific to the new host environment, and may involve CD4-independent engagement of a viral coreceptor conserved among primates

Identifying key drivers of the impact of an HIV cure intervention in sub-Saharan Africa

BACKGROUND:  The properties required of an intervention that results in eradication or control of HIV in absence of antiretroviral therapy (ART-free viral suppression) to make it cost-effective in low income settings are unknown. METHODS:  We used a model of HIV and ART to investigate the effect of introducing an ART-free viral suppression intervention in 2022 in an example country of Zimbabwe. We assumed that the intervention (cost: $500) would be accessible for 90$300 million (8.7% saving). An intervention of this efficacy costing anything up to $1400 is likely to be cost-effective in this setting. CONCLUSION:  Interventions aimed at curing HIV have the potential to improve overall disease burden and to reduce costs. Given the effectiveness and cost of ART, such interventions would have to be inexpensive and highly effective

Viral Dynamics of Acute HIV-1 Infection

Viral dynamics were intensively investigated in eight patients with acute HIV infection to define the earliest rates of change in plasma HIV RNA before and after the start of antiretroviral therapy. We report the first estimates of the basic reproductive number (R0), the number of cells infected by the progeny of an infected cell during its lifetime when target cells are not depleted. The mean initial viral doubling time was 10 h, and the peak of viremia occurred 21 d after reported HIV exposure. The spontaneous rate of decline (α) was highly variable among individuals. The phase 1 viral decay rate (δI = 0.3/day) in subjects initiating potent antiretroviral therapy during acute HIV infection was similar to estimates from treated subjects with chronic HIV infection. The doubling time in two subjects who discontinued antiretroviral therapy was almost five times slower than during acute infection. The mean basic reproductive number (R0) of 19.3 during the logarithmic growth phase of primary HIV infection suggested that a vaccine or postexposure prophylaxis of at least 95% efficacy would be needed to extinguish productive viral infection in the absence of drug resistance or viral latency. These measurements provide a basis for comparison of vaccine and other strategies and support the validity of the simian immunodeficiency virus macaque model of acute HIV infection