Quantitative and Qualitative Distinctions between HIV-1 and SIV Reservoirs: Implications for HIV-1 Cure-Related Studies

Abstract

The persistence of the latent viral reservoir is the main hurdle to curing HIV-1 infection. SIV infection of non-human primates (NHPs), namely Indian-origin rhesus macaques, is the most relevant and widely used animal model to evaluate therapies that seek to eradicate HIV-1. The utility of a model ultimately rests on how accurately it can recapitulate human disease, and while reservoirs in the NHP model behave quantitatively very similar to those of long-term suppressed persons with HIV-1 (PWH) in the most salient aspects, recent studies have uncovered key nuances at the clonotypic level that differentiate the two in qualitative terms. In this review, we will highlight differences relating to proviral intactness, clonotypic structure, and decay rate during ART between HIV-1 and SIV reservoirs and discuss the relevance of these distinctions in the interpretation of HIV-1 cure strategies. While these, to some degree, may reflect a unique biology of the virus or host, distinctions among the proviral landscape in SIV are likely to be shaped significantly by the condensed timeframe of NHP studies. ART is generally initiated earlier in the disease course, and animals are virologically suppressed for shorter periods before receiving interventions. Because these are experimental variables dictated by the investigator, we offer guidance on study design for cure-related studies performed in the NHP model. Finally, we highlight the case of GS-9620 (Vesatolimod), an antiviral TLR7 agonist tested in multiple independent pre-clinical studies in which virological outcomes may have been influenced by study-related variables.

Keywords: HIV-1 cure studies; NHP models of HIV-1; SIV reservoir.

Figure 1

Typical periods of ART initiation in NHP studies. (A) Dynamics of plasma VL and viral DNA across the 6 Fiebig stages of acute HIV-1 infection. The period in disease course at which ART was initiated in several NHP studies employing HIV cure therapeutics is noted in red. In most clinical scenarios, HIV-1 is diagnosed as chronic infection. (B) The contribution of CD4 T cell maturation states harboring the reservoir across different Fiebig stages of acute HIV-1/SIV and at differing periods of ART initiation in published NHP cure-related studies.

Figure 2

ART-induced viral DNA decay rate, proviral clonotypic landscape, quantities of unintegrated viral DNA, and typical intervention windows are major factors that differentiate NHP pre-clinical from clinical studies. (A) Decay rates of viral DNA in SIV NHP (blue) and HIV-1 (red) after initiating ART. Distinct phases of viral genome decay are noted, with the majority of interventions tested in the NHP model of HIV implemented significantly earlier after virologic suppression than those of clinical trials (examples noted in red by the “NCT” clinical trial number). (B) Longitudinal dynamics of the clonal landscape of integrated viral DNA and quantities of unintegrated forms of viral DNA that exist as 2-LTR circles. In general, the majority of pre-clinical NHP studies are performed on reservoirs that are less clonotypically skewed and comprise higher levels of unintegrated viral DNA compared to reservoirs of participants enrolled in clinical trials. This illustration has been adapted from Kumar et al and the concepts of this illustration are derived from the work of this study [84].

Figure 3

Distinctions in genomic integrity between HIV-1 and SIV reservoirs measured by the intact proviral DNA assay (IPDA). Representative differences in proviral landscapes of long-term suppressed PLWH and ART-suppressed NHPs illustrated by the intact proviral DNA assay. Major distinctions in NHP include higher frequencies of intact viral genomes, lower frequencies of viral genomes harboring large deletions, and higher frequencies of highly mutated viral genomes that cannot be detected by conventional IPDA probes. This illustration has been adapted from Bender et al. and the concepts are derived from the work of this study [88].