Kinetics and specificities of the T helper-cell response to gp120 in the asymptomatic stage of HIV-1 infection

Peripheral blood mononuclear cells from 36 asymptomatic HIV-1 seropositive individuals were tested longitudinally for in vitro T–cell proliferation and IL–2 production in response to synthetic peptides spanning the entire gp120 of HIV–1. At baseline, significant T–cell proliferation to pooled and individual peptides was observed in 15 of the 36 donors. After 12 months, proliferate responses to peptide pools were lost or decreased significantly in most donors. Responses appeared to fluctuate over time: at 12 months new recognition sites were detected in four of 10 donors showing T–cell proliferation at baseline, as well as in five of 15 donors with no previous proliferative responses. IL–2 production appeared to be a more sensitive and longer preserved parameter of T–helper cell function: at baseline the majority of donors with no T–cell proliferation produced IL–2 in response to pooled peptides. This response was not decreased significantly after 12 months. The overall patterns of response to both pooled and individual peptides were heterogeneous among donors. Multiple recognition sites were detected in both variable and conserved regions of gp120, but no pool or individual peptide was recognized by all responders. Functional T–cell responses were not statistically correlated to CD4° cell percentile and absolute numbers

Simian immunodeficiency virus (SIV)-specific CD8+ cytotoxic T lymphocyte responses of naive and vaccinated cynomolgus macaques infected with (SIV)mac32H(J5): quantitative analysis by in vitro antigenic stimulation.

Detailed analyses of simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocyte (CTL) responses in vaccinated and infected macaques may help to clarify the role of CTL immunity in protection against lentiviruses. Here, the optimal conditions for the measurement of SIV Gag-specific CTL were investigated by bulk and limiting dilution assays of peripheral blood mononuclear cells (PBMC) from naive and vaccinated cynomolgus macaques (Macaca fascicularis) infected with SIVmac32H(J5). In vitro restimulation was generally required for CTL detection. Selective activation of CD8+ and MHC-restricted SIV Gag-specific CTL was induced by stimulation with autologous para-formaldehyde-fixed B-lymphoblastoid cell lines infected with a recombinant vaccinia virus expressing SIV Gag. Applied to limiting dilution assays, antigenic stimulation reproducibly demonstrated SIV Gag-specific CTL precursors (CTLp) in PBMC of all animals studied, including those lacking significant responses in standard bulk CTL assays

Vaccine-induced virus-neutralizing antibodies and cytotoxic T cells do not protect macaques from experimental infection with simian immunodeficiency virus SIVmac32H (J5).

To gain further insight into the ability of subunit vaccines to protect monkeys from experimental infection with simian immunodeficiency virus (SIV), two groups of cynomolgus macaques were immunized with either recombinant SIVmac32H-derived envelope glycoproteins (Env) incorporated into immune-stimulating complexes (iscoms) (group A) or with these SIV Env iscoms in combination with p27gag iscoms and three Nef lipopeptides (group B). Four monkeys immunized with recombinant feline immunodeficiency virus Env iscoms served as controls (group C). Animals were immunized intramuscularly at weeks 0, 4, 10, and 16. Two weeks after the last immunization, monkeys were challenged intravenously with 50 monkey 50% infectious doses of virus derived from the J5 molecular clone of SIVmac32H propagated in monkey peripheral blood mononuclear cells. High titers of SIV-neutralizing antibodies were induced in the monkeys of groups A and B. In addition, p27gag-specific antibodies were detected in the monkeys of group B. Vaccine-induced cytotoxic-T-lymphocyte precursors against Env, Gag, and Nef were detected on the day of challenge in the monkeys of group B. Env-specific cytotoxic-T-lymphocyte precursors were detected in one monkey from group A. In spite of the observed antibody and T-cell responses, none of the monkeys was protected from experimental infection. In addition, longitudinal determination of cell-associated virus loads at weeks 2, 4, 6, 9, and 12 postchallenge revealed no significant differences between vaccinated and control monkeys. These findings illustrate the need to clarify the roles of the different arms of the immune system in conferring protection against primate lentivirus infections

Decline of simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocytes in the peripheral blood of long-term nonprogressing macaques infected with SIVmac32H-J5.

The evolution of simian immunodeficiency virus (SIV)–specific cytotoxic T lymphocyte precursors (CTLps) and their relationship with virus replication were studied in SIV‐infected macaques. After primary viremia, 3 of 8 macaques l

Predictors of Virologic Failure in HIV/AIDS Patients Treated with Highly Active Antiretroviral Therapy in Brasília, Brazil During 2002–2008

Little data exists concerning the efficacy of the antiretroviral therapy in the Federal District in Brazil, therefore in order to improve HIV/AIDS patients’ therapy and to pinpoint hot spots in the treatment, this research work was conducted. Of 139 HIV/AIDS patients submitted to the highly active antiretroviral therapy, 12.2% failed virologically. The significant associated factors related to unresponsiveness to the lentiviral treatment were: patients’ place of origin (OR = 3.28; IC95% = 1.0–9.73; P = 0.032) and Mycobacterium tuberculosis infection (RR = 2.90; IC95% = 1.19–7.02; P = 0.019). In the logistic regression analysis, the remaining variables in the model were: patients’ birthplace (OR = 3.28; IC95% = 1.10–9.73; P = 0.032) and tuberculosis comorbidity (OR = 3.82; IC95% = 1.19–12.22; P = 0.024). The patients enrolled in this survey had an 88.0% therapeutic success rate for the maximum period of one year of treatment, predicting that T CD4+ low values and elevated viral loads at pretreatment should be particularly considered in tuberculosis coinfection, besides the availability of new antiretroviral drugs displaying optimal activity both in viral suppression and immunological reconstitution

Virus replication and evolution drive the kinetics and specificity of SIV-specific cytotoxic T lymphocyte.

SIV (simian immunodeficiency virus) infection of cynomolgus macaques provides an excellent model for investigating the basis of protective immunity against HIV (human immunodeficiency virus). We explored the protective role of cytotoxic T lymphocytes (CTL) against the pathogenic molecular clone SIVmac-J5. Vaccine-induced CTL precursors (CTLp) against Env, Gag or Nef did not protect macaques against intravenous challenge. However, detection of Rev-specific CTLp in infected macaques was associated with effective virus containment. Furthermore, CTL against an immunodominant Gag/p26 epitope (amino acids 242-250) resulted in the emergence of a mutant virus that uniformly replaced wild-type virus in the spleen and partially escaped recognition. During primary infection, CTLp detection in blood coincided with decreasing viremia. After 12 months, two outcomes emerged. In one group of macaques, persistent viremia was associated with high viral load in lymphoid organs and declining CD4+ T-cell counts. CTLp were maintained in asymptomatic macaques, but declined in the symptomatic phase of infection. In a second group, loss of detectable viremia was associated with low-level virus reservoirs in lymphoid organs, asymptomatic status and maintained CD4+ T-cell counts. CTLp peaked in the first 4 months of infection and subsequently declined in this group. These studies provide insights into the complex interplay between virus replication and host immunity