OBJECTIVES: To investigate which immune parameters, such as antibodies against HIV-1 specificities, or viral parameters, such as p24 antigenemia, are predictive of disease progression. STUDY DESIGN: We performed studies on serum collected from individuals exhibiting two extremes of disease evolution--67 fast progressors (FP) and 182 nonprogressors (NP)--at their enrollment. After a 1- to 2-year clinical follow-up of 104 nonprogressors after their enrollment, we could determine the best serologic predictors for disease progression. METHODS: We investigated levels of antibodies to tetanus toxoid and to HIV antigens including Env, Gag, Nef, and Tat proteins, as well as p24 antigenemia, viremia, CD4 cell count, and interferon-alpha (IFN-alpha) titers in FPs and NPs, and we correlated these data with clinical and biologic signs of progression. RESULTS: p24 Antigenemia, a marker of viral replication, and anti-Tat antibodies were highly and inversely correlated in both groups (P < .001). Furthermore, anti-p24 antibodies and low serum IFN-alpha levels were correlated to the NP versus the FP cohort. Finally, among NPs, only antibodies to Tat and not to the other HIV specificities (Env, Nef, Gag) were significantly predictive of clinical stability during their follow-up. CONCLUSION: Antibodies toward HIV-1 Tat, which are inversely correlated to p24 antigenemia, appear as a critical marker for a lack of disease progression. This study strongly suggests that rising anti-Tat antibodies through active immunization may be beneficial in AIDS vaccine development to control viral replication.

AIDS Vaccines↗

PubMedDate not supplied

Safety and immunogenicity of HIV-1 Tat toxoid in immunocompromised HIV-1-infected patients.

OBJECTIVES: To antagonize the deleterious effects of the HIV-1 toxin extracellular Tat on uninfected immune cells, we developed a new strategy of anti-HIV-1 vaccine using an inactivated but immunogenic Tat (Tat toxoid). Tat toxoid has been assayed for safety and immunogenicity in seropositive patients. METHOD: The phase I vaccine clinical trial testing Tat toxoid preparation in Seppic Isa 51 oil adjuvant was performed on 14 HIV-1-infected asymptomatic although biologically immunocompromised individuals (500-200 CD4+ cells/mm3). RESULTS: Following as many as 8 injections, no clinical defects were observed. All patients exhibited an antibody (Ab) response to Tat, and some had cell-mediated immunity (CMI) as evaluated by skin test in vivo and T-cell proliferation in vitro. CONCLUSION: These results provide initial evidence of safety and potency of Tat toxoid vaccination in HIV-1-infected individuals.

AIDS Vaccines↗

PubMedDate not supplied

HIV-1 regulatory protein tat induces RNA binding proteins in central nervous system cells that associate with the viral trans-acting-response regulatory motif.

OBJECTIVES: To investigate some of the cellular consequences of HIV-1 Tat expression in human astrocytic cells. This study is based on evidence that cellular factors play a critical role in facilitating transcriptional activation by Tat through its interaction with the trans-acting-response (TAR) RNA element and upstream HIV-1 long terminal repeat (LTR) promoter binding site. STUDY DESIGN-METHODS: Using the previously established astrocytic cell line of human origin stably transfected with Tat cDNA, we analyzed the formation of a nucleoprotein complex consisting of three cellular proteins associated with TAR RNA using ultraviolet (UV) crosslinking and glutathione-S-transferase (GST) pull-down assays. RESULTS: UV crosslinking experiments reveal that the molecular masses of the proteins range from 50 to 62 kd. Transient transfection studies demonstrate that the presence of these proteins correlates with the ability of Tat to transactivate the HIV-1 LTR in the absence of the trinucleotide bulge, a region within TAR that has been shown to be important for Tat-TAR interaction. A combination of GST pull-down assays and RNA binding studies demonstrates that the 50-kd protein interacts with both Tat and TAR and is likely to be NF-kappa B p50. CONCLUSIONS: Taken together, these data suggest that in the absence of a functional Tat binding site such as TAR (which tethers the viral protein to the RNA), cellular protein NF-kappa B p50 may be able to bring Tat into the RNA binding complex Tat has been shown to activate expression of a variety of cellular genes that may not contain a binding site for Tat but do contain binding sites for NF-kappa B family members. The results presented in this study may be relevant for Tat-mediated transactivation of cellular as well as viral genes, both of which might contribute to the central nervous system damage associated with HIV-1 infection.

Astrocytes↗

PubMedDate not supplied

The value of early home assessment in identifying risk in children who were very low birth weight.

Demographic, medical risk variables and information obtained during early home assessments of very low birth weight infants and their families were compared in their ability to identify subsequent risk in 4-year-old children who were very low birth weight. The home assessment data were equal or better than the demographic risk variables in efficacy and efficiency.

Child Development↗