Rare Control of SIVmac239 Infection in a Vaccinated Rhesus Macaque

Abstract

Effector memory T cell (T) responses display potent antiviral properties and have been linked to stringent control of simian immunodeficiency virus (SIV) replication. Since recurrent antigen stimulation drives the differentiation of CD8 T cells toward the T phenotype, in this study we incorporated a persistent herpesviral vector into a heterologous prime/boost/boost vaccine approach to maximize the induction of T responses. This new regimen resulted in CD8 T-biased responses in four rhesus macaques, three of which controlled viral replication to <1,000 viral RNA copies/ml of plasma for more than 6 months after infection with SIVmac239. Over the course of this study, we made a series of interesting observations in one of these successful controller animals. Indeed, in vivo elimination of CD8αβ T cells using a new CD8β-depleting antibody did not abrogate virologic control in this monkey. Only after its CD8α lymphocytes were depleted did SIV rebound, suggesting that CD8αα but not CD8αβ cells were controlling viral replication. By 2 weeks postinfection (PI), the only SIV sequences that could be detected in this animal harbored a small in-frame deletion in nef affecting six amino acids. Deep sequencing of the SIVmac239 challenge stock revealed no evidence of this polymorphism. However, sequencing of the rebound virus following CD8α depletion at week 38.4 PI again revealed only the six-amino acid deletion in nef. While any role for immunological pressure on the selection of this deleted variant remains uncertain, our data provide anecdotal evidence that control of SIV replication can be maintained without an intact CD8αβ T cell compartment.

The dynamics of simian immunodeficiency virus after depletion of CD8+ cells

“…Indeed, a very recent new result cast an unexpected twist that will need further investigation. Using a new antibody that depletes CD8 β + cells (and not CD8α+ cells, as in previous studies), Martins et al found in at least one animal that depletion of CD8 β + cells had no impact on viral load, while in the same animal depletion of CD8α+ cells led to the well‐known rapid increase in viral load.…”

“…One of the most common uses of CD8+ cell depletion is to investigate the effects of vaccine protocols. In these studies, a SIV vaccination and challenge protocol is implemented and when control of virus below the levels of placebo is found, often CD8+ cell depletion is performed to ascertain if these cells are important in the observed control . Another common use is in a model of SIV‐induced encephalitis (SIVE).…”

“…In these last four studies, viral load control or not was an outcome of natural infection. Four other studies tested different vaccine protocols in which viral control is elicited by the vaccine, and then analyzed the importance of CD8+ cells in the immune mechanism responsible for viral control by depleting them (Metzner et al, Martins et al, Hansen et al, and Amara et al). Finally, one study analyzed viral control during early treatment with broadly neutralizing antibodies (Nishimura et al).…”

“…In these studies, a SIV vaccination and challenge protocol is implemented and when control of virus below the levels of placebo is found, often CD8+ cell depletion is performed to ascertain if these cells are important in the observed control. [52][53][54][55][56][57][58][59] Another common use is in a model of SIV-induced encephalitis (SIVE). Depletion of CD8+ cells in primary infection leads to high viral loads and rapid progression, including a high incidence of SIVE, more than double in comparison to infection in nondepleted animals.…”

Extensive CD8β depletion does not prevent control of viral replication or protection from challenge in macaques chronically infected with a live attenuated simian immunodeficiency virus

“…One approach to better define the antiviral role of CD8+ T cells in vivo is to administer a CD8β-specific depleting mAb, as this should selectively deplete CD8αβ+ T cells without removing CD8αα+ lymphocytes or other non-T cell populations. Indeed, two recent studies using the CD8β-specific mAb CD8β255R1 in rhesus macaques provide evidence that CD8αβ+ T cells can be specifically depleted in vivo (40, 41).…”