Chronic Alcohol Consumption Results in Higher Simian Immunodeficiency Virus Replication in Mucosally Inoculated Rhesus Macaques

ABSTRACT Cytotoxic T-lymphocyte (CTL) responses are crucial for the control of immunodeficiency virus replication. Possible involvement of a dominant single epitope-specific CTL in control of viral replication has recently been indicated in preclinical AIDS vaccine trials, but it has remained unclear if multiple epitope-specific CTLs can be involved in the vaccine-based control. Here, by following up five rhesus macaques that showed vaccine-based control of primary replication of a simian immunodeficiency virus, SIVmac239, we present evidence indicating involvement of multiple epitope-specific CTL responses in this control. Three macaques maintained control for more than 2 years without additional mutations in the provirus. However, in the other two that shared a major histocompatibility complex haplotype, viral mutations were accumulated in a similar order, leading to viral evasion from three epitope-specific CTL responses with viral fitness costs. Accumulation of these multiple escape mutations resulted in the reappearance of plasma viremia around week 60 after challenge. Our results implicate multiple epitope-specific CTL responses in control of immunodeficiency virus replication and furthermore suggest that sequential accumulation of multiple CTL escape mutations, if allowed, can result in viral evasion from this control.

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Chronic Alcohol Consumption Generates a Vulnerable Immune Environment During Early SIV Infection in Rhesus Macaques

Alcoholism Clinical and Experimental Research ◽

10.1111/j.1530-0277.2008.00730.x ◽

2008 ◽

Vol 32 (9) ◽

pp. 1583-1592 ◽

Cited By ~ 20

Author(s):

Maria Cecilia G. Marcondes ◽

Debbie Watry ◽

Michelle Zandonatti ◽

Claudia Flynn ◽

Michael A. Taffe ◽

...

Keyword(s):

Alcohol Consumption ◽

Rhesus Macaques ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

Siv Infection

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Simian immunodeficiency virus types 1 and 2 (SIV mnd 1 and 2) have different pathogenic potentials in rhesus macaques upon experimental cross-species transmission

Journal of General Virology ◽

10.1099/vir.0.005181-0 ◽

2009 ◽

Vol 90 (2) ◽

pp. 488-499 ◽

Cited By ~ 13

Author(s):

Sandrine Souquière ◽

Richard Onanga ◽

Maria Makuwa ◽

Ivona Pandrea ◽

Paul Ngari ◽

...

Keyword(s):

T Cell ◽

Simian Immunodeficiency Virus ◽

Virus Replication ◽

Rhesus Macaques ◽

Natural Infection ◽

Cell Depletion ◽

T Cell Depletion ◽

Viral Loads ◽

Cell Counts ◽

Immunodeficiency Virus

The mandrill (Mandrillus sphinx) is naturally infected by two types of simian immunodeficiency virus (SIV): SIVmnd types 1 and 2. Both of these viruses cause long-term, non-progressive infections in their natural host despite high plasma viral loads. This study assessed the susceptibility of rhesus macaques to infection by these two types of SIVmnd and compared the virological and basic immunological characteristics of the resulting infections with those observed in natural infection in mandrills. Whilst both SIVmnd types induced similar levels of virus replication during acute infection in both mandrills and macaques, they produced a more pronounced CD4+ T-cell depletion in rhesus macaques that persisted longer during the initial stage of infection. Pro-inflammatory cytokine responses were also induced at higher levels in rhesus macaques early in the infection. During the chronic phase of infection in mandrills, which in this case was followed for up to 2 years after infection, high levels of chronic virus replication did not induce significant changes in CD4+ or CD8+ T-cell counts. In rhesus macaques, the overall chronic virus replication level was lower than in mandrills. At the end of the follow-up period, although the viral loads of SIVmnd-1 and SIVmnd-2 were relatively similar in rhesus macaques, only SIVmnd-1-infected rhesus macaques showed significant CD4+ T-cell depletion, in the context of higher levels of CD4+ and CD8+ T-cell activation, compared with SIVmnd-infected mandrills. The demonstration of the ability of both SIVmnd types to induce persistent infections in rhesus macaques calls for a careful assessment of the potential of these two viruses to emerge as new human pathogens.

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Macaques Vaccinated with Simian Immunodeficiency Virus SIVmac239Δnef Delay Acquisition and Control Replication after Repeated Low-Dose Heterologous SIV Challenge

Journal of Virology ◽

10.1128/jvi.00041-10 ◽

2010 ◽

Vol 84 (18) ◽

pp. 9190-9199 ◽

Cited By ~ 53

Author(s):

Matthew R. Reynolds ◽

Andrea M. Weiler ◽

Shari M. Piaskowski ◽

Holly L. Kolar ◽

Ann J. Hessell ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Virus Replication ◽

Rhesus Macaques ◽

Chronic Phase ◽

Hiv Vaccine ◽

Rank Test ◽

Mucosal Transmission ◽

Immunodeficiency Virus ◽

Control Virus ◽

And Control

ABSTRACT An effective human immunodeficiency virus (HIV) vaccine will likely need to reduce mucosal transmission and, if infection occurs, control virus replication. To determine whether our best simian immunodeficiency virus (SIV) vaccine can achieve these lofty goals, we vaccinated eight Indian rhesus macaques with SIVmac239Δnef and challenged them intrarectally (i.r.) with repeated low doses of the pathogenic heterologous swarm isolate SIVsmE660. We detected a significant reduction in acquisition of SIVsmE660 in comparison to that for naïve controls (log rank test; P = 0.023). After 10 mucosal challenges, we detected replication of the challenge strain in only five of the eight vaccinated animals. In contrast, seven of the eight control animals became infected with SIVsmE660 after these 10 challenges. Additionally, the SIVsmE660-infected vaccinated animals controlled peak acute virus replication significantly better than did the naïve controls (Mann-Whitney U test; P = 0.038). Four of the five SIVsmE660 vaccinees rapidly brought virus replication under control by week 4 postinfection. Unfortunately, two of these four vaccinated animals lost control of virus replication during the chronic phase of infection. Bulk sequence analysis of the circulating viruses in these animals indicated that recombination had occurred between the vaccine and challenge strains and likely contributed to the increased virus replication in these animals. Overall, our results suggest that a well-designed HIV vaccine might both reduce the rate of acquisition and control viral replication.

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