Autoproliferation in HIV-1-infected patients undergoing active HIV-1-specific immunotherapy.

We have observed a treatment-associated autoproliferative response in cultured peripheral blood mononuclear cells (PBMC) of asymptomatic HIV-1-infected subjects receiving a gp120-depleted, inactivated HIV-1 antigen in incomplete Freund's adjuvant (IFA; HIV-1 Immunogen). The frequency and magnitude of the autoproliferative response appeared to be dose-related (P < 0.05), and was not observed in subjects receiving IFA alone. Immunophenotyping of the proliferating cells demonstrated the presence of both CD4+ and CD8+ lymphocytes, with the CD4+ blasts almost exclusively expressing the CD45RO+ phenotype. A comparison of this response with the HIV-1-specific antigen stimulation responses in this cohort revealed a significant correlation between increases in HIV-1-specific cell-mediated immunity and autoproliferation (r2 = 0.61, P < 0.001). These findings suggest that immunization with the HIV-1 Immunogen induces an autoproliferative response that may reflect changes in HIV-1-specific cell-mediated immunity in infected individuals.     

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.     

Detection and enumeration of circulating HIV-1-specific memory B cells in HIV-1-infected patients

Memory B cells are long-living cells that circulate throughout the body and differentiate into plasma cells after stimulation by antigens, cytokines, and direct cell-to-cell interaction in lymphoid tissues. For HIV-1-infected patients, we assessed whether in vitro polyclonal B cell activation that induces immunoglobulin secreting cells (SCs) also generates HIV-1-specific resting B cells to synthesize antibodies specific to HIV-1. To this end, highly purified B cells from 10 HIV-1-untreated patients were cultured with or without mouse fibroblastic cells expressing the CD40 ligand in the presence of IL-2 and IL-10. The percentage of immunoglobulin SCs we obtained by using the B cell-CD40L stimulation system was equal to 55% to 98% of the circulating memory B cells. Moreover, the anti-HIV-1 IgG, IgA, or IgM antibody SCs represented 1 x 10-2 to 1 x 10-3 of the total immunoglobulin SCs. The anti-HIV-1-specific antibodies detected in cell culture supernatants were directed to gag-, pol-, and env-encoded viral proteins. We found that in AIDS patients, HIV-1-specific resting memory B cells circulate in the blood and can be quantified by their anti-HIV-1 antibody secretion after strong B cell polyclonal stimulation.     

Dysregulation of beta-chemokines in the lungs of HIV-1-infected patients

The beta-chemokines, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, monocyte chemotactic protein (MCP)-1 and regulated-on-activation normal T cell, expressed and secreted (RANTES) are not only chemotactic for mononuclear cells but may be important in suppression of HIV-1 replication through competitive binding to the chemokine receptor, CCR5, which is critical to viral entry. In this study, bronchoalveolar cells (BACs) and autologous peripheral blood mononuclear cells (PBMCs) were obtained from HIV-1-infected participants who did not manifest clinical signs of lung disease with peripheral CD4 T-cell count >200/mm(3) (n = 7, group with high CD4 count), or CD4 T-cell count <200/mm(3) (n = 12, group with low CD4 count), and from healthy study subjects (n = 5). The capacity to express beta-chemokines and CCR5 was assessed. Induction of MIP-1 alpha by lipopolysaccharide (LPS) in BAC of HIV-1-infected study subjects from the low CD4 group was less than BAC from healthy study subjects (p <.001), and also was less than in BACs from the group with a high CD4 group (p <.001). Moreover, the intracellular expression of MIP-1 alpha in LPS-induced monocytes of HIV-1-infected patients was significantly less than that from healthy study subjects (p <.01). In addition, spontaneous expression of mRNAs for CCR5 and MIP-1 alpha in BAC was significantly lower in HIV-1-infected patients compared with in healthy study subjects (p <.03 and p <.02, respectively). In contrast to the findings with MIP-1 alpha, LPS stimulated MCP-1 in BAC from the group of HIV-1-infected patients with high CD4 count was significantly higher than healthy study subjects (p <.001). These dysregulations in the ability to express beta-chemokines by BAC may be important in the progression of HIV-1 infection in the lung.     

Evolution of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy from 2000 to 2010

Prevalence and predictors of transmitted drug resistance (TDR), defined as the presence of at least one WHO surveillance drug resistance mutation (SDRM), were investigated in antiretroviralna?ve HIV-1-infected patients, with a genotypic resistance test (GRT) performed ≤6 months before starting cART between 2000 and 2010. 3163 HIV-1 sequences were selected (69% subtype B). Overall, the prevalence of TDR was 12% (13.2% subtype B, 9% non-B). TDR significantly declined overall and for the single drug classes. Older age independently predicted increased odds of TDR, whereas a more recent GRT, a higher HIV-RNA and C vs. B subtype predicted lower odds of TDR.     

A case-control study of gynecomastia in HIV-1-infected patients receiving HAART

Gynecomastia has been reported to occur in HIV-infected patients receiving HAART. A retrospective case-control study was conducted to determine risk factors associated with this condition. Two control patients were randomly chosen for each of 23 case patients identified. An efavirenz-containing regimen was strongly associated with the development of gynecomastia (odds ratio, 20; P < .001). Case patients were not more likely to have lipodystrophy, low testosterone levels, chronic infection with hepatitis B or C virus, or liver dysfunction compared with control patients. None of these factors altered the efavirenz-associated risk when analyzed by multiple logistic regression. Efavirenz appears to be strongly associated with gynecomastia in HIV-infected patients receiving HAART.     

Efficacy and immunologic responses to influenza vaccine in HIV-1-infected patients

Influenza vaccine is recommended for HIV-1-infected patients. The present prospective study was conducted to evaluate the clinical efficacy and immunologic responses to the vaccine. From November 1 to December 27, 2002, 262 HIV-1-infected patients received a trivalent influenza subunit vaccine, whereas 66 did not. Influenza illness occurred in 16 vaccinated and 14 nonvaccinated patients (incidence = 6.1% [95% confidence interval (CI): 4%-10%] in vaccinated vs. 21.2% [CI: 13%-35%] in nonvaccinated persons, P < 0.001; relative risk = 0.29 [CI: 0.14-0.55]). Influenza vaccine provided clinically effective protection against influenza illness in HIV-1-infected patients. In baseline antibody-negative patients, anti-H1 and anti-H3 antibody responses to the vaccination were significant in those patients with a CD4 count >200 cells/muL compared with those with a CD4 count <200 cells/muL (P < 0.05). In contrast, in baseline antibody-positive patients, good antibody responses were observed irrespective of CD4 counts, like the healthy controls. Based on these results, annual vaccination is recommended. Specific CD4 responses correlated with HIV-1 viral load (VL), especially in patients treated with highly active antiretroviral therapy (HAART) compared with those without HAART (P < 0.01), although the clinical efficacy did not correlate with HIV-1 VL. HAART may enhance the immunologic efficacy of influenza vaccine.     

Cognitive function in HIV-1-infected drug users

Loss of cognitive ability, the most common neuropsychological complication in HIV-1 disease, may influence compliance with treatment and has been associated with decreased functional capacity, as well as an increased risk of mortality. In HIV-1-infected drug users, cognitive impairment affecting attention, memory, planning of complex tasks, information processing, and motor processes, has been reported, similar to findings in predominantly HIV-1-infected nondrug-using cohorts. The issue of whether early signs of cognitive dysfunction can be identified in asymptomatic HIV-1-infected drug users remains controversial. Evaluation of potential confounding factors, such as drug abuse, age, education, nutritional status, which may influence cognitive function, is essential for determining the dominant cause of neuropsychological abnormalities. There is evidence for a time-limited, protective effect against the development of AIDS dementia with zidovudine therapy. The potential ability of other therapies (e.g., antioxidants, B-complex vitamins) to prevent neuronal damage and protect the brain remains to be determined.     

Outcome of ICSI in HIV-1-infected women

BACKGROUND: Since 2001, French law has permitted the use of assisted reproductive technology in human immunodeficiency virus (HIV)-1 infected women under strict conditions. This report describes a preliminary series of seropositive women who underwent assisted reproduction treatment at our facility. To minimize contamination of culture media, equipment, and therefore of male gametes and embryos, we chose to perform ICSI in all cases. The outcome of ICSI was compared with the outcome in an age-matched group of non-HIV-1-infected women. Since several previous reports have indicated that HIV infection may be associated with a decrease in spontaneous fertility, our goal was also to assess the fertility status of the HIV-1-infected women entering our ICSI programme. METHODS: The French law governing the use of assisted reproduction protocols in HIV-1-infected women was strictly applied. The inclusion criteria were absence of ongoing disease, CD4((+)) count >200 cells/mm(3), and stable HIV-1 RNA level. Since mean age at the time of ICSI was higher in HIV-1-infected women than in the overall group of non-HIV-infected women, we compared outcome data in HIV-1-infected women (group I) to a group of non-HIV-1-infected women matched with regard to age and follicle retrieval period (group II) as well as to the overall group of women who underwent ICSI at our institution (group III). RESULTS: A total of 66 ovarian stimulations was performed in 29 HIV-1-infected-infected women. The percentage of cancelled cycles was higher in infected women than in matched controls (15.2 versus 4.9%, P < 0.05). The duration of ovarian stimulation (13.3 versus 11.7 days, P < 0.05) and amount of recombinant FSH injected (2898 versus 2429 IU, P < 0.001) were also higher in infected women. The number of retrieved oocytes, mature oocytes, and embryos obtained as well as embryo quality was similar in all groups. The fertilization rate was higher in infected women than in matched controls (67 versus 60%, P < 0.01). The pregnancy rate was not significantly different between groups I and II (16.1 versus 19.6%) in spite of the fact that the number of embryos transferred was purposefully restricted in the HIV-1-infected group to minimize multiple pregnancy (2.0 versus 2.4, not significant). CONCLUSION: The results of this preliminary series of ICSI cycles in HIV-1-infected women indicate that optimal ovarian stimulation is slightly more difficult to achieve than in matched seronegative women. However, when criteria for oocyte retrieval were fulfilled, ICSI results were similar to those of age-matched controls.     

Correlation of T-lymphocyte subpopulations with immunological markers in HIV-1-infected Indian patients

Progressive HIV disease is characterized by CD4 T cell decline and activation of the immune system. We aimed to study the quantitative alterations in the naive (CD45RA+CD62L+), memory/effector (CD45RO+) and activated (HLA-DR+CD38+) T-lymphocyte subpopulations in antiretroviral treatment naive, HIV-1 infected Indian patients by three-color multi-parametric flow cytometry. The association of different CD4+ and CD8+ T cell subsets with the immunological markers- CD4+ and CD8+ T cell percentages was examined by calculating the partial correlation coefficients. We also observed significant differences in the expression of different CD4+ and CD8+ T-cell subsets among the two groups of patients formed using the median CD4+ T cell percentage value (15%) of the study population. The correlations of different CD4+ and CD8+ T cell subsets reflected the quantitative alterations in the T-lymphocyte subpopulations and activation of the immune system during HIV-infection. The study outcome also emphasizes the significance of the CD38+CD8+ T-lymphocyte subset as a prognostic marker for HIV management and ART monitoring in resource-limited settings of developing countries like India.     

The potential place of chloroquine in the treatment of HIV-1-infected patients

BACKGROUND: Chloroquine has been reported to be endowed with anti-HIV-1 activity. We previously found its anti-HIV-1 activity to be additive to that of of the hydroxyurea plus didanosine combination. OBJECTIVES: Here we wish to present reported data on chloroquine's effects other than its antiretroviral activity, that may be of benefit in the therapy of HIV-1-infected individuals. RESULTS: (1) Chloroquine exerts an inhibitory effect on several AIDS-opportunistic pathogens, at least in vitro and, in some cases, in murine infections. (2) The drug exerts an inhibitory effect on the synthesis of several pro-inflammatory cytokines that may play a pathogenic role in the progression of HIV infection. (3) The drug has the potential to restrict tissular iron accumulation that may play a negative role in HIV infection. (4) The drug has practical advantages, as it is widely distributed, inexpensive and not stigmatizing. (5) We hypothesized that the drug, if given to HIV-positive breast-feeding mothers, may be of potential benefit in decreasing the rate of mother-to-child transmission of HIV-1. CONCLUSION: in view of the above-given data, combination therapy with chloroquine warrants clinical studies in HIV-1-infected patients, mainly in the setting of resource-poor countries.     

Diabetes, insulin resistance, and dementia among HIV-1-infected patients

OBJECTIVES: Metabolic complications have been associated with HIV-1 infection and with long-term use of antiretroviral (ARV) medications. In some studies, such complications have been linked to cardiovascular events, yet limited data exist concerning metabolic complications and dementia. The objective of this study was to examine the relationship between HIV-associated dementia (HAD) and diabetes among patients with HIV-1 infection. DESIGN: Cross-sectional analysis of entry data for a longitudinal cohort study. METHODS: A total of 203 participants who were enrolled in the Hawaii Aging with HIV Cohort between October 2001 and November 2003 served as the study population. Research case definitions of HAD were determined in consensus conferences by a panel that included neurologists, neuropsychologists, and a geriatrician. Diabetes was determined by self-report or a fasting glucose level > 125 mg/dL. RESULTS: Participants' ages ranged between 20-76 years at enrollment with approximately one-half aged >/=50 years. After adjustment for important covariates including age, education, ethnicity, CD4 lymphocyte count, duration of HIV infection, and protease inhibitor-based ARV therapy, we found a statistically significant association of diabetes with HAD (odds ratio 5.43, 1.66-17.70). A significant association remained after adjustment for other vascular risk factors. Among participants without diabetes, fasting glucose levels were higher with increasing impairment category. CONCLUSIONS: Within the Hawaii Aging with HIV Cohort, a longitudinal study enriched with older HIV-1-infected individuals, diabetes is associated with prevalent dementia. This finding is not fully explained by age or coexisting vascular risk factors. Evaluation of underlying mechanisms is warranted.     

Dendritic cells from HIV-1-infected patients naturally express HIV-1 gp120 V3 loop-derived peptide ligands

Little is known of the peptide ligands expressed in vivo on antigen-presenting cells (APC) or of the APC lineages involved. In this study we have addressed this question using HLA-DRβ1*0101-restricted CD4 T cell clones (TLC) specific for a synthetic peptide based on the HIV-1 gp120 V3 loop consensus sequence for the Clade B isolates predominantly found in European and North American patients. These TLC were found to respond, in a dose-dependent manner, to freshly isolated HIV-infected patient APC in the absence of exogenously added peptides. Further APC purification showed that the naturally expressed peptide ligands were present in both the APC lineages shown to be infected with the virus and were most strongly detectable on purified blood dendritic cells. Peptides based on consensus sequences of viruses isolated from one of the patients over the period when naturally expressed peptide ligands could be detected were all found to stimulate TLC proliferation. These studies, therefore, show that peptide ligands derived from natural infection are detectable on APC lineages, particularly on dendritic cells which play an important role in the immune response to viruses. Even small differences in sequence between the vaccine isolate and the natural infection, if they occur in the key residues of protective T cell epitopes, could therefore have a profound effect on the efficacy of vaccines against viruses with high rates of mutation.