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. 2002 Aug;76(15):7661-71.
doi: 10.1128/jvi.76.15.7661-7671.2002.

Experimental coinfection of rhesus macaques with rhesus cytomegalovirus and simian immunodeficiency virus: pathogenesis

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Experimental coinfection of rhesus macaques with rhesus cytomegalovirus and simian immunodeficiency virus: pathogenesis

Getachew Sequar et al. J Virol. 2002 Aug.

Abstract

Human cytomegalovirus (HCMV) possesses low pathogenic potential in an immunocompetent host. In the immunosuppressed host, however, a wide spectrum of infection outcomes, ranging from asymptomatic to life threatening, can follow either primary or nonprimary infection. The variability in the manifestations of HCMV infection in immunosuppressed individuals implies that there is a threshold of host antiviral immunity that can effectively limit disease potential. We used a nonhuman primate model of CMV infection to assess the relationship between CMV disease and the levels of developing anti-CMV immunity. Naive rhesus macaques were inoculated with rhesus cytomegalovirus (RhCMV) followed 2 or 11 weeks later by inoculation with pathogenic simian immunodeficiency virus SIVmac239. Two of four monkeys inoculated with SIV at 2 weeks after inoculation with RhCMV died within 11 weeks with simian AIDS (SAIDS), including activated RhCMV infection. Neither animal had detectable anti-SIV antibodies. The other two animals died 17 and 27 weeks after SIV inoculation with either SAIDS or early lymphoid depletion, although no histological evidence of activated RhCMV was observed. Both had weak anti-SIV antibody titers. RhCMV antibody responses for this group of monkeys were significantly below those of control animals inoculated with only RhCMV. In addition, all animals of this group had persistent RhCMV DNA in plasma and high copy numbers of RhCMV in tissues. In contrast, animals that were inoculated with SIV at 11 weeks after RhCMV infection rarely exhibited RhCMV DNA in plasma, had low copy numbers of RhCMV DNA in most tissues, and did not develop early onset of SAIDS or activated RhCMV. SIV antibody titers were mostly robust and sustained in these monkeys. SIV inoculation blunted further development of RhCMV humoral responses, unlike the normal pattern of development in control monkeys following RhCMV inoculation. Anti-RhCMV immunoglobulin G levels and avidity were slightly below control values, but levels maintained were higher than those observed following SIV infection at 2 weeks after RhCMV inoculation. These findings demonstrate that SIV produces long-lasting insults to the humoral immune system beginning very early after SIV infection. The results also indicate that anti-RhCMV immune development at 11 weeks after infection was sufficient to protect the host from acute RhCMV sequelae following SIV infection, in contrast to the lack of protection afforded by only 2 weeks of immune response to RhCMV. As previously observed, monkeys that were not able to mount a significant immune response to SIV were the most susceptible to SAIDS, including activated RhCMV infection. Rapid development of SAIDS in animals inoculated with SIV 2 weeks after RhCMV inoculation suggests that RhCMV can augment SIV pathogenesis, particularly during primary infection by both viruses.

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Figures

FIG. 1.
FIG. 1.
Representative examples of RhCMV histopathology in macaques coinfected with RhCMV and SIV. (A) Tissue from the sentinel monkey (29863) showing evidence of multifocal interstitial pneumonia and containing cells with intranuclear and intracytoplasmic RhCMV inclusions (arrows). (B) Markedly atrophic thymus from 30458 (group I), in which fibrous connective tissue has replaced much of the thymus and in which large numbers of large cells containing RhCMV inclusions were observed (arrows). (C) Disseminated meningitis in the brain of 30437 (group I). Multiple cells were positive (brown) for RhCMV IE1 expression, including both cells with inclusions and histologically normal cells. The morphology of the IE1-positive cells was consistent with that of macrophages.
FIG. 2.
FIG. 2.
Longitudinal analysis of SIV plasma viral load. The copy numbers of SIV genomes (expressed as copy numbers per milliliter of plasma) for each monkey, grouped according to inoculation protocol, are plotted relative to time after RhCMV inoculation (week 0). Arrows, times of SIV inoculation. The limit of detection was 50 copies.
FIG. 3.
FIG. 3.
Longitudinal analysis of RhCMV IgG immune responses. Individual RhCMV IgG immune responses (A450), grouped according to inoculation protocol, are plotted relative to time after RhCMV inoculation (week 0). Inoculation with SIV and/or RhCMV at week 11 is indicated.
FIG. 4.
FIG. 4.
Longitudinal analysis of RhCMV IgG AI. Individual RhCMV AI, grouped according to inoculation protocol, are plotted relative to weeks after RhCMV inoculation (week 0). Inoculation with SIV and/or RhCMV at week 11 is indicated.
FIG. 5.
FIG. 5.
Longitudinal analysis of RhCMV plasma DNA copy number. Individual RhCMV plasma DNA copy numbers (log copy number per milliliter), grouped according to inoculation protocol, are plotted relative to time after RhCMV inoculation (week 0). Inoculation with SIV and/or RhCMV at week 11 is indicated. The limit of sensitivity was 2.3 (dashed lines).

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