[PMC free article] [PubMed] [Google Scholar] 84

[PMC free article] [PubMed] [Google Scholar] 84. directed to linear epitopes in the V3 loop. Virus-specific cellular immune responses also were generated, as judged by the presence of Gag-specific gamma interferon (IFN-)-generating cells. These cellular immune responses required the inclusion of DNABx08 in the immunization modality, since few or no IFN–producing cells were detected in animals that received either VLPBx08 or ALVACBx08 alone. The results demonstrate the feasibility of generating neutralizing antibodies and cellular immune responses that target an R5 main HIV-1 isolate by vaccination in primates. Accumulating evidence supports a Rimonabant hydrochloride positive role for neutralizing antibodies and CD8+ cytotoxic T lymphocytes (CTL) in the antiviral immune response to human immunodeficiency computer virus type 1 (HIV-1) and simian immunodeficiency computer virus (SIV) (33, 44). The ability to generate antibodies that neutralize a broad spectrum of main HIV-1 isolates has proven to be one of the more difficult difficulties for vaccine development (44). Major targets for neutralizing antibodies are the surface gp120 and transmembrane gp41 envelope glycoproteins of the computer virus (12). Antibodies that bind these viral glycoproteins with adequate affinity and appropriate specificity can prevent HIV-1 from entering host cells (32, 41, 45, 71, 78, 83, Rimonabant hydrochloride 84) and have provided potent protection against contamination in passive-antibody experiments in animal models (2, 20, 22, 35, 38, 76). Attempts at inducing cross-reactive neutralizing antibodies through vaccination have, however, experienced limited success. Most attempts have focused on the envelope glycoproteins of a small number of T-cell line-adapted (TCLA) strains of computer virus. Even though envelope glycoproteins of those strains generate high titers of neutralizing antibodies, those antibodies mostly target strain-specific epitopes in the third variable cysteine-cysteine loop (V3 loop) of gp120 (10, 45) and have been highly specific for TCLA strains of computer virus (23, 50). Importantly, the antibodies have failed to neutralize main isolates (4, 5, 10, 37) and often possess little or no detectable neutralizing activity against heterologous TCLA strains (5, 10). The B-cell response leading to HIV-1-specific neutralizing antibody production could be fundamentally different for main isolates compared to TCLA strains. For example, whereas TCLA strains are highly sensitive to neutralization by V3 loop-specific antibodies (26, 68), the V3 loop on main isolates is usually occluded by N-linked glycans and tertiary folds around the native gp120 molecule (30, 62, 73C75, 90, 91), making it a poor target for neutralizing antibodies (9, 77, 86). The envelope glycoproteins of TCLA strains and many, but not all, main isolates also exhibit different coreceptor preferences for computer virus access. Generally speaking, main isolates utilize either CCR5 (R5), CXCR4 (X4), or both Rimonabant hydrochloride coreceptors (R5/X4) whereas all TCLA strains have the X4 phenotype (6, 7, 67). For reasons that are poorly understood, most transmitted strains of HIV-1 have an R5 phenotype (63, 87) and, although no association has been found between coreceptor preference and neutralization sensitivity (31, 43, 81), it seems prudent to target R5 strains when designing candidate HIV-1 vaccines. Much of what is known about the neutralization epitopes on main isolates comes from studies of three human monoclonal antibodies (MAbs), immunoglobulin G1b12 (IgG1b12), 2G12, and 2F5. Each of these MAbs can neutralize diverse main isolates (12) and, when combined, exhibit synergistic neutralizing activity (36). A vaccine that generates antibodies equal to the combination of these specificities is usually highly desired and deserving of intense investigation. Regrettably, the corresponding epitopes have proven to be poorly immunogenic in natural infections and in experimentally immunized animals. Other neutralization epitopes are present on main isolates that Mouse monoclonal to CD4.CD4, also known as T4, is a 55 kD single chain transmembrane glycoprotein and belongs to immunoglobulin superfamily. CD4 is found on most thymocytes, a subset of T cells and at low level on monocytes/macrophages are less conserved. The latter epitopes account for the sporadic, low-level neutralization of heterologous isolates by sera from infected individuals (46, 58, 89). They might also account for the potent neutralization of main isolates by autologous serum samples that are obtained months or years after the time of computer virus isolation (29, 48, 56, 58, 89), which would require the cognate epitopes to be immunogenic and well uncovered around the computer virus.