Moses Otsyula

Immediate zidovudine treatment protects simian immunodeficiency virus-infected newborn macaques against rapid onset of AIDS.

Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a practical animal model of pediatric AIDS. Intravenous inoculation of rhesus newborns with uncloned SIVmac resulted in a high virus load, no antiviral immune responses, severe immunodeficiency, and a high mortality rate within 3 months. In contrast, immediate oral zidovudine (AZT) treatment of SIV-inoculated rhesus newborns either prevented infection or resulted in reduced virus load, enhanced antiviral immune responses, a low frequency of AZT-resistant virus isolates, and delayed disease progression with negligible toxicity. These results suggest that early chronic AZT treatment of human immunodeficiency virus-exposed newborns may have benefits that outweigh its potential side effects.

Virus-induced immunosuppression is linked to rapidly fatal disease in infant rhesus macaques infected with Simian immunodeficiency virus

Six newborn rhesus macaques were experimentally infected with pathogenic Simian immunodeficiency virus of macaques (SIVmac251), and three newborn macaques were infected with avirulent SIVmac1A11. The former developed rapidly fatal simian AIDS and died within 26 wk of age, whereas the latter remained clinically normal. Infant monkeys that developed rapidly progressive disease had rapid declines in CD4+ cells and were unable to mount IgG and IgA antibody responses to SIV or to an unrelated antigen, tetanus toxoid. IgM antibody responses were near normal to both SIV-specific and nonspecific antigens. Cytotoxic T lymphocyte (CTL) responses to SIV envelope were observed in animals infected with either virulent or avirulent SIV. These studies demonstrated that virulent SIVmac infection induced a rapid immunosuppression that was both SIV-specific and nonspecific in nature. The observation that virulent strains of SIV can rapidly induce a global immunosuppression provides one explanation for the rapid disease course in some HIV-infected children and supports the strategy of early and vigorous antiviral drug therapy to alter the disease course even if this does not prevent infection.

Cytomegalovirus and simian immunodeficiency virus coinfection: longitudinal study of antibody responses and disease progression.

Antibody titers to rhesus cytomegalovirus (RhCMV) were prospectively analyzed over a period of 68 weeks in a longitudinal serosurvey of 17 RhCMV-seropositive rhesus macaques (Macaca mulatta) experimentally coinfected with simian immunodeficiency virus (SIV). These were compared with anti-RhCMV titers in 18 animals that were also naturally infected with RhCMV but not infected with SIV. Fluctuations in anti-RhCMV antibody titers were observed within 5 weeks of SIV inoculation, and two distinct patterns of RhCMV antibody response were observed in SIV-infected animals. Animals showing a progressive decline in anti-RhCMV immunoglobulin G (IgG) exhibited the most rapid disease progression, coincident with low anti-SIV and anti-tetanus toxoid IgG responses, high levels of p27 antigen in the plasma, and short survival. Animals exhibiting a more stable CMV-specific response after SIV inoculation had the least rapid disease course. Anti-RhCMV antibody titers in SIV-uninfected animals remained relatively stable during the period of study. Evidence that preinoculation immunologic measures predicted postinoculation outcome was equivocal.

Mucosal immunization with a live, virulence-attenuated simian immunodeficiency virus (SIV) vaccine elicits antiviral cytotoxic T lymphocytes and antibodies in rhesus macaques.

An effective AIDS vaccine must protect against sexual transmission of human immunodeficiency virus (HIV). Therefore, vaccine regimens which stimulate antiviral immunity in the genital tract as well as in peripheral blood and systemic lymphoid tissues are needed. Here, we describe a method of immunization by direct inoculation of the vaginal submucosa with a live attenuated SIV, SIVmac1A11. Immunization by this route generated low levels of SIV‐specific IgG and IgA antibodies in serum and vaginal secretions and viral specific cytotoxic T lymphocyte (CTL) activity in peripheral blood.

Neutralizing antibody responses in Africa green monkeys naturally infected with simian immunodeficiency virus (SIVagm)

Abstract: This study assessed the magnitude and cross‐reactivity of the neutralizing antibody response generated by natural SIV infection in wild‐caught African green monkeys. Neutralizing antibodies of variable potency, sometimes exceeding a titer of 1:1,000, were detected in 20 of 20 SIV‐seropositive African green monkeys in Kenya. Detection of those neutralizing antibodies was dependent on the strain of virus and the cells used for assay, where the most sensitive detection was made with SIVagml532 in Sup T1 cells. Potent neutralization of SIVagml532 was seen with contemporaneous autologous serum. Potent neutralization was also detected with laboratory‐passaged SIVmac251 and SIVsmB670, but not with SIVsmE660 and two additional strains of SIVagm. Serum samples from rhesus macaques (Macaca mulatta) experimentally infected with either SIVmac251 or SIVsmE660 were capable of low‐level neutralization of SIVagm. These results indicate that natural infection with SIV can generate strain‐specific neutralizing antibodies in African green monkeys. They also indicate that some neutralization determinants of SIVagm are partially shared with SIV strains that arose in sooty mangabys and were subsequently transmitted to rhesus macaques.