Rapid and Irreversible CD4(+) T-Cell Depletion Induced by the Highly Pathogenic Simian/Human Immunodeficiency Virus SHIV(DH12R) Is Systemic and Synchronous

Highly pathogenic simian/human immunodeficiency virus chimeric viruses are known to induce a rapid, irreversible depletion of CD4(+) T lymphocytes in the peripheral blood of acutely infected macaque monkeys. To more fully assess the systemic effects of this primary virus infection, specimens were collected serially between days 3 and 21 postinfection from variety of lymphoid tissues (lymph nodes, thymus, and spleen) and gastrointestinal tract and examined by DNA and RNA PCR, in situ hybridization, and immunohistochemical assays. In addition, the lymphoid tissues were evaluated by fluorescence-activated cell sorting. Virus infection was initially detected by DNA PCR on day 3 postinfection in lymph node samples and peaked on day 10 in the T-lymphocyte-rich areas of this tissue. CD4(+) T-cell levels remained stable through day 10 in several lymphoid tissue specimens examined but fell precipitously between days 10 and 21. In situ terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays revealed the accumulation of apoptotic cells during the second week of infection in both lymph nodes and thymus, which colocalized, to a large extent, to sites of both virus replication and CD4(+) T-lymphocyte loss

Preexposure passive transfer predicts plasma antibody levels prevent HIV-I aquisition

Background: It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). During the past four years, a new generation of potent broadly reacting neutralizing monoclonal antibodies (mAbs) have been isolated from HIV-I infected individuals. These mAbs typically exhibit great breadth and potency against heterologous HIV isolates when assayed for neutralization in vitro. The passive transfer of anti-HIV l neutralizing antibodies conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. Methods: In this study, five recently isolated potent and broadly acting anti-HIV neutralizing mAbs, interacting with the HIV l gp 120 CD4 binding site (VRCO I, 45-46 m^2 and 3BNC 117) or dependent on the gp120 N332 glycan, (10-1074 and PGTl2l) were individually administered to 60 rhesus monkeys, which were challenged intrarectally 24 hours later with either of two different R5-tropic SHIVs. Results: Of the 5 neutralizing mAbs evaluated, PGT121 was clearly the most effective against both viruses. In addition to measuring the plasma concentrations of the different mAbs at the time of challenge and their respective in vivo half lives, the corresponding protective neutralization titers were also determined. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus acquisition in 50% of the exposed monkeys was approximately 1:100. Conclusion: These results are informative for establishing a threshold level of protective neutralizing activity to be induced by a prophylactic HIV I vaccine

Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques

It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti–HIV-1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (∼1:100) and potentially achievable by vaccination

Transfer of neutralizing IgG to macaques 6 h but not 24 h after SHIV infection confers sterilizing protection: Implications for HIV-1 vaccine development

Passive transfer of high-titered antiviral neutralizing IgG, known to confer sterilizing immunity in pig-tailed monkeys, has been used to determine how soon after virus exposure neutralizing antibodies (NAbs) must be present to block a simian immunodeficiency virus (SIV)/HIV chimeric virus infection. Sterilizing protection was achieved in three of four macaques receiving neutralizing IgG 6 h after intravenous SIV/HIV chimeric virus inoculation as monitored by PCR analyses of and attempted virus isolations from plasma, peripheral blood mononuclear cell, and lymph node specimens. In the fourth animal, the production of progeny virus was suppressed for >4 weeks. A delay in transferring NAbs until 24 h after virus challenge resulted in infection in two of two monkeys. These results suggest that even if a vaccine capable of eliciting broadly reactive NAbs against primary HIV-1 were at hand, the Abs generated must remain at, or rapidly achieve, high levels within a relatively short period after exposure to virus to prevent the establishment of a primate lentivirus infection