Immune clearance of highly pathogenic SIV infection

Abstract

Established infections with the human and simian immunodeficiency viruses (HIV, SIV) are thought to be permanent with even the most effective immune responses and anti-retroviral therapies (ART) only able to control, but not clear, these infections1–4. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that ~50% of rhesus macaques (RM) vaccinated with SIV protein-expressing Rhesus Cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviremic control of infection with highly pathogenic SIVmac2395. Here, we demonstrate that regardless of route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and hematogenous viral dissemination, and that replication-competent SIV persists in multiple sites for weeks to months. However, over time, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma or tissue-associated virus using ultrasensitive assays, and loss of T cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive RT-PCR and PCR analysis of tissues from RhCMV/SIV vector-protected RM necropsied 69–172 weeks after challenge did not detect SIV RNA or DNA over background, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million hematolymphoid cells to naïve RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T cell-mediated immune surveillance elicited and maintained by CMV vectors.

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

“…However, many persistent viral infections such as CMV and EBV in humans lead to CD8 T-cell responses reaching a higher magnitude than most acute infections. Hansen et al (42,43) have recently reported that rhesus macaques vaccinated with persistent rhesus CMV expression vectors containing simian immunodeficiency virus (SIV) proteins elicit durable viral control after challenge with SIV. The studies suggested that the SIV control was linked to a large magnitude of CD8 T cells generated and maintained by the persistent vector at sites of viral entry (mucosa) and at other sites of potential viral dissemination.…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…Along with the evidence that HIV infections impair the thymic output, this furthermore reveals the retention of T-cells in established chronic infections that can expand substantially 30,31 . The demonstration that virus titers strongly rise following depletion of CD8 + T-cells in SIV infected macaques [32][33][34] and that protective immune responses can be elicited upon vaccinating SIV infected Rhesus macaques 35 further underscore the strong effector capacity of CD8 + T-cells in established chronic infections.…”

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…A beneficial role for CD8 + T cells in blocking acquisition is less apparent, although this possibility cannot be dismissed. Intriguing studies suggest that CD8 + T-cell responses elicited by a replicating viral vector vaccine can clear a nascent simian immunodeficiency virus (SIV) infection in roughly half of vaccinated nonhuman primates (18). These responses alone did not block acquisition but could contribute to such an effect if combined with certain humoral responses.…”