Redefining the HIV-infectious window period in the chimpanzee model: evidence to suggest that viral nucleic acid testing can prevent blood-borne transmission.

BACKGROUND: Although it is rare, blood-transmitted HIV infection can occur when a donor presents in the window period between HIV-1 exposure and the first appearance of detectable p24 antigen. STUDY DESIGN AND METHODS: To study this seronegative window period, a chimpanzee (X034) was inoculated with 38 median tissue culture infective doses of HIV-1 IIIB; serum and peripheral blood mononuclear cells were obtained one to two times per week for 12 weeks and then biweekly for 12 weeks. Infectivity was monitored by the detection of serum HIV RNA, cell-associated HIV DNA, p24 antigen, and anti-HIV and by co-culture methods. RESULTS: No HIV markers were noted until 5 weeks after inoculation, at which time virus was isolated and HIV RNA and DNA were detected in plasma and cells, respectively. Anti-HIV and HIV p24 antigen were not present until 8 weeks after inoculation. Plasma and cells obtained from Chimpanzee X034 3 or 4 weeks after exposure were then sequentially inoculated into a second chimpanzee (X176); no HIV infection was observed in this animal during serial follow-up for 24 weeks after each inoculation. In contrast, when the fifth-week HIV-1 RNA- and DNA-positive sample was inoculated, Chimpanzee X176 was unequivocally infected with HIV-1. CONCLUSIONS: Nucleic acid testing narrowed the seronegative window by 3 weeks (37%). More important, there was no demonstrable infectivity in either plasma or peripheral blood mononuclear cells obtained before molecular markers were detectable. This suggests that the infectious window may be considerably shorter than the total window as measured from exposure and that nucleic acid testing might not only shorten the seronegative window, but totally prevent transfusion-transmitted HIV infection.

Prevention of HIV-1 infection in chimpanzees by gp120 V3 domain-specific monoclonal antibody.

The acquired immunodeficiency syndrome (AIDS) is the late-stage clinical manifestation of long-term persistent infection with the human immunodeficiency virus type 1 (HIV-1). Immune responses directed against the virus and against virus-infected cells during the persistent infection fail to mediate resolution of the infection. As a result, a successful AIDS vaccine must elicit an immune state that will prevent the establishment of the persistent infection following introduction of the virus into the host. The third hypervariable (V3) domain of the HIV-1 gp120 envelope glycoprotein is a disulphide-linked closed loop of about 30 amino acids which binds and elicits anti-HIV-1 type-specific virus-neutralizing antibodies. The in vitro characteristics of anti-V3 domain antibody suggest that this antibody could by itself prevent HIV-1 infection in vivo, an idea supported by chimpanzee challenge studies in which protection against the HIV-1 persistent infection seemed to correlate with the presence of anti-V3 domain antibody. Here we directly demonstrate the protective efficacy of anti-V3 domain antibody in vivo and propose that this antibody is potentially useful as both a pre- and post-exposure prophylactic agent.

Prevention of HIV infection by passive immunization with HIV immunoglobulin.

The use of a human immunodeficiency virus (HIV) immune globulin (HIVIG) in prevention of HIV infection in chimpanzees was investigated in the hope of ultimate application to interruption of vertical transmission. In previous experiments, no protection was observed when relatively high challenge doses were used. This study shows that HIVIG protected against a challenge dose (10 CID50) tenfold lower than that used previously. The protected animal remained free of HIV infection as determined by cocultivation and by polymerase chain reaction (PCR), and did not mount a primary immune response detectable by enzyme-linked immunosorbant assay (ELISA) and neutralization assays. These results imply that HIV vaccines should induce neutralizing antibody and may not need to induce cell-mediated immunity in order to be protective against exposure to HIV. They also provide an experimental basis for the conduct of clinical trials to evaluate prevention of maternal-infant transmission by HIVIG.

T-cell responses to human immunodeficiency virus (HIV) and its recombinant antigens in HIV-infected chimpanzees.

Peripheral blood lymphocytes from chimpanzees infected for 3 months to more than 3 years with human immunodeficiency virus (HIV) had normal T-cell proliferative responses after stimulation with a variety of recall antigens and mitogens, indicating that HIV infection does not cause detectable immunological impairment in chimpanzees. This finding contrasts with that obtained in HIV-infected humans, who often have impaired T-cell reactivity. Peripheral blood lymphocytes from most HIV-infected chimpanzees that were studied also had strong proliferative responses to purified HIV as well as to HIV envelope glycoproteins isolated from the virus, to recombinant HIV envelope glycoproteins gp120 and gp41, and to HIV gag protein p24. The HIV-specific T-cell responses in HIV-infected chimpanzees may contribute to prevention of the development of acquired immunodeficiency syndrome in this species.