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Because milk-borne transmission of human immunodeficiency virus (HIV) diminishes the benefits of perinatal antiviral drug therapy in developing countries, we have developed a new strategy to prevent postnatal and, possibly, intrapartum virus transmission in a primate model. Eight neonatal rhesus macaques were exposed orally to pathogenic simian-human immunodeficiency virus (SHIV); 4 neonates were then given intramuscular postexposure prophylaxis with 3 anti-HIV human neutralizing monoclonal antibodies (nMAbs) with potent cross-clade and cross-group neutralization activity. Untreated infants experienced high viral RNA levels and CD4+ T-cell losses and died (median survival time, 5.5 weeks). In contrast, all 4 nMAb-treated neonates were protected from infection (P =.028); their plasma, peripheral blood mononuclear cells, and lymph nodes remained virus negative for >1 year. These data are important for designing clinical trials in human neonates and have general implications for AIDS vaccine development, as the epitopes recognized by the 3 nMAbs are conserved among diverse primary isolates.

We evaluated the protective role of passively transferred circulating antibodies in protecting non-human primates against experimental rotavirus infection. Pooled sera with rotavirus-specific IgG titers that were either high (1:10,000), intermediate (1:300), or negative (<1:25) were infused i.v. into naïve pigtailed macaques (ages 3-6 months). Rotavirus-specific IgG could be detected in the sera at 18 h in all animals infused with antibody-containing serum, and fecal IgG titers could be detected only in animals given high-titer pooled sera. When orally challenged with 106fluorescent-forming units of a simian rotavirus strain, YK-1, at 18 h after serum transfer, control animals shed virus starting 1-3 days after challenge and continued to shed virus at high titers for 6-8 days, whereas passively immunized macaques did not shed virus or had delayed shedding at low titers for only a limited time. The observation that passively transferred antibodies can suppress or delay viral infection in rotavirus-challenged pigtailed macaques has important implications for the design and testing of parenteral candidate rotavirus vaccines.

Chimpanzees are susceptible to infection with human immunodeficiency virus (HIV)—1; however, infected animals usually maintain normal numbers of CD4+ T lymphocytes and do not develop immunodeficiency. We have examined 10 chronically infected HIV-1—positive chimpanzees for evidence of progressive infection. In addition to 1 animal that developed AIDS, 3 chimpanzees exhibit evidence of progressive HIV infection. All progressors have low CD4+ T cell counts (<200 cells/µL), severe CD4:CD8 inversion, and marked reduction in interleukin-2 receptor expression by CD4+ T cells. In comparison with HIV-positive nonprogressor chimpanzees, progressors have higher plasma and lymphoid virus loads, greater CD38 expression in CD8+/HLA-DR+ T cells, and greater serum concentrations of soluble tumor necrosis factor type II receptors and β2-microglobulin, all markers of HIV progression in humans. These observations show that progressive HIV-1 infection can occur in chimpanzees and suggest that the pathogenesis of progressive infection in this species resembles that in humans.

We have established models for intrapartum and milk-borne HIV transmission by orally challenging neonatal macaques with chimeric simian–human immunodeficiency viruses (SHIVs). This allowed us to test safety and efficacy of passive immunization with human neutralizing monoclonal antibodies (nmAbs), which had been isolated from HIV clade B-infected individuals and which target conserved, functionally important epitopes. The nmAbs studied were F105 or IgG1b12, b12 for short (directed against the CD4 binding site), 2G12 (anti-gp120), 2F5 and 4E10 (both anti-gp41). Out of 16 newborn macaques challenged orally with different SHIV strains, 11 were completely protected by triple or quadruple nmAb combinations, even by post-exposure prophylaxis. In vitro, the combination of b12, 2G12, 2F5 and 4E10 potently neutralized primary HIV isolates of clades A, B, C, and D. Our data suggest that passive immunization with currently available anti-HIV clade B nmAbs could play a role in preventing transmission of non-clade B isolates through breastfeeding. We furthermore conclude that the epitopes recognized by the nmAbs in our successful passive immunization studies are important determinants for protection and provide targets for developing neutralizing antibody-response-based, active AIDS vaccines.

Induction of strong cellular immunity will be important for AIDS vaccine candidates. Natural infection with wild-type Listeria monocytogenes ( Lm), an orally transmitted organism, is known to generate strong cellular immunity, thus raising the possibility that live attenuated Lm could serve as a vaccine vector. We sought to examine the potential of live attenuated Lm to induce cellular immune responses to HIV Gag. Rhesus macaques were immunized with Lmdd-gag that expresses HIV gag and lacks two genes in the d-alanine ( d-ala) synthesis pathway. Without this key component of the bacterial cell wall, vaccine vector replication critically depends on exogenous d-ala. Lmdd-gag was given to animals either solely orally or by oral priming followed by intramuscular (i.m.) boosting; d-ala was co-administered with all vaccinations. Lmdd-gag and d-ala were well tolerated. Oral priming/oral boosting induced Gag-specific cellular immune responses, whereas oral priming/i.m. boosting induced systemic as well as mucosal anti-Gag antibodies. These results suggest that the route of vaccination may bias anti-Gag immune responses either towards T-helper type 1 (Th1) or Th2 responses; overall, our data show that live attenuated, recombinant Lmdd-gag is safe and immunogenic in primates.

Heterologous prime/boost regimens have the potential for raising high levels of immune responses. Here, we report that DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster has controlled a highly pathogenic immunodeficiency virus challenge in a Rhesus macaque model. Both the DNA and rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks and a single rMVA booster at 24 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These highly promising findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the AIDS epidemic.

Passive immunization with synergistic combinations of human monoclonal antibodies (mAbs) directed against conserved epitopes of the human immunodeficiency virus (HIV) envelope completely protected 13 out of 16 rhesus monkeys challenged intravenously or orally with chimeric simian-human immunodeficiency virus (SHIV) strains; partial protection was seen in another two. A high degree of protection was seen among orally challenged neonates. Thus, we propose that passive immunization with synergistic combinations of neutralizing human mAbs may be effective in preventing maternal HIV transmission when given as post-exposure prophylaxis at birth and as prophylaxis against milk-borne transmission. Because we only used mAbs with well-defined epitope specificities, our studies also yield key information for designing AIDS vaccines: the correlates of immune protection. Vaccine strategies that can evoke antibody responses to epitopes recognized by the mAbs used in our primate studies could be important components of successful AIDS vaccines.

Successes for neutralizing antibodies (nAbs) against the human immunodeficiency virus (HIV) include potent cross-clade neutralization of primary virus isolates by human neutralizing monoclonal antibodies (nmAbs) targeting conserved envelope epitopes. Furthermore, passively administered combinations of human nmAbs prevented infection in primates, indicating that epitopes recognized by such nmAbs are key determinants for protection. Lastly, in the absence of CD8 + T cells, nAbs may act as a second line of defense during chronic infection. Taken together, these results argue for generating nAb response-based prophylactic and/or therapeutic AIDS vaccines. We suggest that the epitopes identified by passive immunization represent excellent targets for the rational design of nAb response-based AIDS vaccines.