Neutralizing antibodies (NAbs) can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS1–4. However, earlier studies of anti-HIV 1 NAbs administered to infected individuals or humanized mice, reported poor control of virus replication and the rapid emergence of resistant variants 5–7. A new generation of anti-HIV 1 monoclonal antibodies (mAbs), possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals 8. These NAbs target different regions of the HIV 1 envelope glycoprotein including the CD4 binding site (bs), glycans located in the V1/V2, V3, and V4 regions, and the membrane proximal external region of gp419–14. We have examined two of the new antibodies, directed to the CD4 bs and the V3 region (3BNC117 and 10-1074 respectively) for their ability to block infection and suppress viremia in macaques infected with the R5 tropic SHIVAD8 virus, which emulates many of the pathogenic and immunogenic properties of HIV 1 during infections of rhesus macaques15,16. Either antibody alone can potently block virus acquisition. When administered individually to recently infected monkeys, the 10-1074 antibody caused a rapid decline in virus loads to undetectable levels for 4 to 7 days, followed by virus rebound during which neutralization resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viremia for 3 to 5 weeks in some long-term chronically SHIV infected animals with low CD4+ T cell levels. A second cycle of anti-HIV 1 mAb therapy, administered to two previously treated animals, successfully controlled virus rebound. These results suggest that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1 infected individuals experiencing immune dysfunction.

Human immunodeficiency virus type 1 (HIV-1) gene expression is activated by Tat, a virally encoded protein. Tat trans-activation requires viral (trans-activation--responsive; TAR) RNA sequences located in the R region of the long terminal repeat (LTR). Existing evidence suggests that Tat probably cooperates with cellular factors that bind to TAR RNA in the overall trans-activation process. A HeLa complementary DNA was isolated and characterized that encodes a TAR RNA-binding protein (TRBP). TRBP activated the HIV-1 LTR and was synergistic with Tat function.

Virus-specific antibodies protect individuals against a wide variety of viral infections. To assess whether human immunodeficiency virus type 1 (HIV-1) envelope-specific antibodies confer resistance against primate lentivirus infections, we purified immunoglobulin (IgG) from chimpanzees infected with several different HIV-1 isolates, and used this for passive immunization of pig-tailed macaques. These monkeys were subsequently challenged intravenously with a chimeric simian-human immunodeficiency virus (SHIV) bearing an envelope glycoprotein derived form HIV-1DH12, a dual-tropic primary virus isolate. Here we show that anti-SHIV neutralizing activity, determined in vitro using an assay measuring loss of infectivity, is the absolute requirement for antibody-mediated protection in vivo. Using an assay that measures 100% neutralization, the titer in plasma for complete protection of the SHIV-challenged macaques was in the range of 1:5-1:8. The HIV-1-specific neutralizing antibodies studied are able to bind to native gp120 present on infectious virus particles. Administration of non-neutralizing anti-HIV IgG neither inhibited nor enhanced a subsequent SHIV infection.

Replication of human immunodeficiency virus type 1 (HIV-1) in most primary cells and some immortalized T-cell lines depends on the activity of the viral infectivity factor (Vif). Vif has the ability to counteract a cellular inhibitor, recently identified as CEM15, that blocks infectivity of Vif-defective HIV-1 variants. CEM15 is identical to APOBEC3G and belongs to a family of proteins involved in RNA and DNA deamination. We cloned APOBEC3G from a human kidney cDNA library and confirmed that the protein acts as a potent inhibitor of HIV replication and is sensitive to the activity of Vif. We found that wild-type Vif inhibits packaging of APOBEC3G into virus particles in a dose-dependent manner. In contrast, biologically inactive variants carrying in-frame deletions in various regions of Vif or mutation of two highly conserved cysteine residues did not inhibit packaging of APOBEC3G. Interestingly, expression of APOBEC3G in the presence of wild-type Vif not only affected viral packaging but also reduced its intracellular expression level. This effect was not seen in the presence of biologically inactive Vif variants. Pulse-chase analyses did not reveal a significant difference in the stability of APOBEC3G in the presence or absence of Vif. However, in the presence of Vif, the rate of synthesis of APOBEC3G was slightly reduced. The reduction of intracellular APOBEC3G in the presence of Vif does not fully account for the Vif-induced reduction of virus-associated APOBEC3G, suggesting that Vif may function at several levels to prevent packaging of APOBEC3G into virus particles.

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques and humans1–12. To determine whether the administration of combination bNAbs during the acute SHIV infection of rhesus macaques might lead to long-term control of virus replication, animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of 2 potent passively transferred bNAbs (3BNC117 and 10-107413,14). Viremia remained undetectable for 56–177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. 4 additional animals maintained their CD4+ T cell counts and very low levels of viremia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the 6 controller macaques. Infusion of a T cell depleting anti-CD8β mAb to the controller animals led to a specific decline in levels of CD8+ T cells and rapid reappearance of plasma viremia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy (cART), beginning on day 3 after infection, experienced sustained rebound plasma viremia when treatment was interrupted. We conclude that passive immunotherapy during the acute SHIV infection differs from cART in that it facilitates the emergence of potent CD8+ T cell immunity able to durably suppress virus replication.

The data suggest that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. Since the majority (approximately 96%) of highly exposed-seronegative individuals tested are not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of novel antiretroviral therapy.

Cross-species transmission of simian immunodeficiency virus from sooty mangabeys (SIVsm) into rhesus macaques, and subsequent emergence of pathogenic SIVmac, required adaptation to overcome restriction encoded by the macaque TRIM5 gene.

Despite the success of potent anti-retroviral drugs in controlling HIV-1 infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 bNAbs can protect mice or macaques against a single high dose challenge with HIV or SIV/HIV chimeric viruses respectively1-8, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Based on the relatively long term protection conferred by Hepatitis A immune globulin, we tested the efficacy of a single injection (20mg/kg) of four anti-HIV-1 neutralizing monoclonal antibodies (MAbs) (VRC01, VRC01-LS, 3BNC117, and 10-10749-12) in blocking repeated weekly low dose virus challenges of the clade B SHIVAD8. Compared to control animals, which required 2 to 6 challenges (median=3 weeks) for infection, a single bNAb infusion prevented virus acquisition for up to 23 weeks. This effect depended on antibody potency and half-life. The highest levels of plasma neutralizing activity and correspondingly, the longest protection, were found in monkeys administered the more potent antibodies, 3BNC117 and 10-1074 (median=13 and 12.5 weeks respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median=8 weeks). The introduction of a mutation that extends antibody half-life into the Fc domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered in to populations at high risk for HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.