A unique cohort of HIV-1-infected long term nonprogressors (LTNP) with normal CD4 ؉ T cell counts and <50 copies͞ml of plasma were prospectively recruited for study. HLA typing revealed a dramatic association between the HLA B*5701 class I allele and nonprogressive infection [85% (11 of 13) vs. 9.5% (19 of 200) in progressors; P < 0.001]. Antigen-specific CD8 ؉ T cells were enumerated by flow cytometric detection of intracellular IFN-␥ in response to HIV antigens and HLA B*57-gag tetramer staining. No quantitative differences in the total HIV-specific CD8 ؉ T cell responses were observed between B*57 ؉ LTNP and five B*57 ؉ progressors (P ‫؍‬ 0.4). Although similar frequencies of peptide specific CD8 ؉ T cells were also found, the gag-specific CD8 ؉ T cell response in the LTNP group was highly focused on peptides previously shown to be B*57-restricted. These findings indicate that, within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease. They also strongly suggest a mechanism of virus specific immunity that directly operates through the B*5701 molecule. Further characterization of qualitative differences in the virus-specific responses that distinguish HLA B*57 ؉ LTNP from progressors may ultimately define mechanisms of effective immune mediated restriction of virus replication.

Although it is presumed that the integration of HIV-1 into the genome of infected CD4+ T lymphocytes allows viral persistence, there has been little direct evidence that CD4+ T cells with integrated provirus function as a latent reservoir for HIV-1 in infected individuals. Using resting CD4+ T-cell populations of extremely high purity and a novel assay that selectively and unambiguously detects integrated HIV-1, we show that resting CD4+ T cells harbouring integrated provirus are present in some infected individuals. However, these cells do not accumulate within the circulating pool of resting CD4+ T cells in the early stages of HIV-1 infection and do not accumulate even after prolonged periods in long-term survivors of HIV-1 infection. These results suggest that because of viral cytopathic effects and/or host effector mechanisms, productively infected CD4+ T cells do not generally survive for long enough to revert to a resting memory state in vivo.

Phase I studies of volunteers not infected with human immunodeficiency virus type 1 (HIV-1) have shown that immunization with envelope subunit vaccine products elicits antibodies that neutralize laboratory-adapted (prototype) HIV-1 strains in vitro. Prototype strains are adapted to grow in continuous (neoplastic) cell lines and are more susceptible to neutralization than are primary isolates cultured in human peripheral blood mononuclear cells. In this study, 50 sera from nine phase I vaccine trials and 16 from HIV-1-infected persons were evaluated for neutralizing antibody activity against 3 laboratory-adapted and 5 primary HIV-1 isolates. Of 50 sera, 49 neutralized at least 1 of the prototype strains; however, none displayed neutralizing activity against primary isolates of HIV-1. Serum from most HIV-1-infected persons neutralized both laboratory-adapted and primary HIV-1 isolates. These data demonstrate a qualitative, or large quantitative, difference in the neutralizing antibody response induced by envelope subunit vaccination and natural HIV-1 infection.

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A series of bicyclams have been shown to be potent and selective inhibitors of human immunodeficiency virus (HIV). The compounds are inhibitory to the replication of various HIV-1 and HIV-2 strains in various human T-cell systems, including peripheral blood lymphocytes, at 0.14-1.4 microM, without being toxic to the host cells at 2.2 mM. The bicyclam JM2763 is active against 3'-azido-3'-deoxythymidine (zidovudine; AZT)-resistant HIV-1 strains and acts additively with AZT. Mechanism of action studies revealed that the bicyclams (i.e., JM2763) interact with an early event of the retrovirus replicative cycle, which could be tentatively identified as a viral uncoating event.

Antibodies generated by candidate HIV-1 vaccines in a phase I clinical trial were assessed for neutralizing activity with a panel of eight well-characterized, genetically diverse clade B primary isolates having an R5 phenotype. The vaccines consisted of one of three different recombinant canarypox vectors expressing membrane-anchored HIV-1(MN)gp120 (ALVAC vCP205, vCP1433, and vCP1452) followed by boosting with a soluble gp160 hybrid consisting of MNgp120 and the majority of gp41 from strain IIIB. Serum samples from a subset of volunteers in each arm of the trial, containing moderate to high titers of neutralizing antibodies to HIV-1 MN, were analyzed. Competition assays with peptides revealed that the majority of neutralizing activity was specific for the MN-V3 loop. Despite MN-specific neutralization titers that sometimes exceeded 1:500, no neutralization of primary isolates was detected and, in some cases, mild infection enhancement was observed. In addition, little or no neutralization of the HIV-1 IIIB heterologous T cell line-adapted strain of virus was detected. These results reinforce the notion that monovalent HIV-1 ENV is a poor immunogen for generating cross-reactive neutralizing antibodies.

This minireview deals with the possible roles of monoamines in feeding and feeding disorders. The introduction sketches the results of earlier studies with local drug injections and selective neurotoxins which provided pharmacological evidence that monoamines can influence food intake and body weight. A table summarizing this evidence is used to list monoamine changes that could underlie anorexia or hyperphagia. It is apparent that abnormalities in the monoamines, along with their cotransmitters, could cause many forms of feeding disorder. It is proposed as a working hypothesis that several varieties of hyperphagia leading to obesity have a common element. This common factor is a change in excitability of a lateral hypothalamic reinforcement system as manifested in self-stimulation at a stimulation-bound feeding site. Understanding this feeding reward-aversion system helps us understand hyperphagia and anorexia. The neurochemistry of reward and aversion involves the monoamines. This paper focuses on dopamine and serotonin. The data support the hypothesis that dopamine systems projecting to the nucleus accumbens and other forebrain areas from the mid-brain ventral tegmental area (VTA) are important for approach and positive reinforcement in ingestive behavior and self-stimulation. Serotonin is hypothesized to facilitate satiety and inhibition of feeding reward in the hypothalamus. The next section abstracts our recent experiments that measured pharmacological and physiological release of the monoamines in the hypothalamus and nucleus accumbens during ingestive behavior and self-stimulation. In vivo microdialysis in freely moving rats suggested the following: (1) Norepinephrine was released in the paraventricular nucleus during the active, feeding period of the circadian cycle. (2) The serotonin metabolite 5-HIAA also increased in the PVN at the same time if there was food to eat. (3) Amphetamine infused into the lateral hypothalamus (LH) by reverse dialysis increased synaptic dopamine, norepinephrine, and serotonin. (4) The anorectic drug d-fenfluramine increased synaptic serotonin in the LH and also increased the dopamine metabolite DOPAC, suggesting that serotonin and dopamine in the LH might contribute to fenfluramine-induced satiety. Local d-fenfluramine injection into the LH or local infusion by reverse dialysis again increased serotonin and decreased 5-HIAA and interfered with local dopamine metabolism as reflected in decreased DOPAC and HVA. (5) Tryptophan, a serotonin precursor, given systemically at an anorectic dose, increased extracellular serotonin in the LH, but this effect was only detectable in food-deprived rats. This was seemingly pH independent (between 5.8 and 8). The passage other cations through CFo is strictly suppressed (even at pH 8 and with 300 mM NaCl in the medium).(ABSTRACT TRUNCATED AT 400 WORDS)

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