Current HIV Research - Volume 6, Issue 1, 2008

Human immunodeficiency virus (HIV)-specific CD8+ T cells can mediate anti-HIV activity by both cytolytic (cytotoxic T lymphocyte or CTL) and non-cytolytic mechanisms (antiviral) and play a crucial role in HIV pathogenesis. Both mechanisms actively contribute to the control of HIV in vivo. The non-cytolytic CD8+T cells from individuals infected with HIV suppress virus replication in CD4+ T cells in vitro by a non-cytolytic mechanism that involves interplay of several chemokines and an unidentified secreted soluble CD8 (+)-cell antiviral factor (CAF). There is immense value of these two distinct CD8 activities in anti-HIV responses and their necessity to be maintained during highly active antiretroviral therapy (HAART). The aim of this review is to provide an overview of some of the novel aspects of CD8+ T cell interactions with HIV, their role in HIV pathogenesis, HAART therapy, HIV disease progression, gene expression and interactions with other cell types during HIV infection.

Mutation of the human immunodeficiency virus by host cells inhibits viral dissemination by creating nonfunctional variants. However, viral mutation does not always eliminate the ability of the virus to disseminate and, in fact, is thought to promote persistence by generating functional mutants that evade immunity or drugs. How and where HIV mutates is not known. Accordingly, where and to what extent variants emerge may be determined by the cell type with optimal mutation apparatus as well as by the properties of the viral genomic sequence itself. Here we considered that HIV, which can infect B cells, may co-opt the Ig somatic hypermutation machinery to generate functional variants and asked whether the HIV envelope coding sequence can diversify in B cells. We show that an HIV envelope coding sequence transfected into B cells mutates in a manner consistent with somatic hypermutation, causing the production of viral protein variants. This result demonstrates that B cells can express and diversify HIV proteins. Thus, B cells may contribute to viral evasion and to the development of multi-drug resistance.

The depletion in circulating dendritic cells (DCs) and inverse correlation with viral load have been described in human immunodeficiency virus (HIV)-infected patients. The aim of this study was to investigate whether the DC blood count in antiretroviral-treated patients might be predictive of viral load control independent of CD4+ T cell count. Plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were enumerated using a newly developed flow cytometric assay based on TruCOUNT. A significant reduction of circulating pDCs and mDCs was detected both in untreated and -treated subjects. The probability of experiencing viral load increase according to pDC, and CD4 count at baseline was evaluated in 39 treated patients. Individuals with lower baseline pDCs were more likely to have an increase of HIV-RNA during the 30 month follow-up in comparison with patients with high pDCs (p <0.001). In particular, the pDC measurement may be useful in the context of a high CD4 count, to distinguish the patients who have virological failure despite high CD4 counts. These findings suggest that in treated patients the enumeration of circulating DCs, especially pDC count, can augment the predictive value of CD4 measurement in predicting virologic failure.

Aim: Mucosal HIV-1 exposure stimulates a variety of mucosal immune responses, including IgA1-mediated virus neutralization, even in the absence of an established infection. We hypothesized that other immune molecules might also contribute to the HIV-1 neutralizing activity observed in the mucosal secretions of HIV-1 exposed uninfected individuals. Methods: Saliva samples were collected from HIV-1 seronegative high-risk female sex workers (FSW) from Nairobi. Samples were also collected from HIV-1 IgG positive FSW and HIV-1 IgG negative low-risk women from the same geographical area. In all samples, IgA2, secretory leukocyte protease inhibitor (SLPI), regulated on activation, normal Tcell expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha and beta (MIP-1αand -β) and monocyte chemoattractant protein-1 (MCP-1) were quantified. The IgA1-depleted saliva samples were subsequently tested for neutralizing capacity in a PBMC-based neutralization assay using a primary HIV-1 clade A isolate to determine biological relevance of the measured molecules. Results: HIV-1 specific neutralization was present in the IgA1-depleted fraction from saliva of both HIV-1 seropositive (9 of 10) and high-risk individuals (36 of 45) but not in HIV-1 IgG-negative control subjects (0 of 8). In the high-risk individuals, higher levels of CC-chemokines were seen in those that could neutralize HIV-1 as compared with those that could not (P<0.05). Conclusion: The HIV-1 neutralizing activity in saliva of HIV-1- exposed high-risk individuals is not only mediated by IgA1, but is also present in IgA1-depleted fractions and is associated with increased levels of CC-chemokines. Such innate immune factors may be important in limiting HIV-1 mucosal transmission.

HIV-1 infection results in an increased risk of malignancy as well as immune suppression. However, analyses of cancer incidence in chronically immunosuppressed transplant recipients and HIV-infected person have demonstrated an unexpected low incidence of certain types of cancer, such as breast cancers, and the mechanism behind this remains unclarified. In this study, we show that most breast cancer cell lines express CXCR4 but are not susceptible to HIV-1 infection. The apoptosis of breast cancer cells is induced by HIV-1 in a viral-dose- and time-dependent manner without productive infection. The apoptosis is induced by R5X4 and X4 HIV-1 but not by R5 HIV-1, and is inhibited by an anti- CXCR4 antibody, an anti-gp120 antibody, AMD3100, or pertussis toxin. The apoptosis is mediated via CXCR4 in breast cancer cells that exhibit conformational heterogeneity in comparison with CXCR4 in T-cells. Furthermore, the gp120 mutant (E370R) with a low CD4 binding ability can specifically induce apoptosis in breast cancer cells but not in T-cells. Taken together, these results indicate that HIV-1 and gp120 can induce breast cancer cell apoptosis through gp120- CXCR4 interaction without a CD4-induced conformational change of gp120, and may lead to a novel HIV-1-based therapy for breast cancer.

(i) To compare early decrease of HIV plasma viral load (pVL) after two standard combinations of highly active antiretroviral therapy (HAART). (ii) To evaluate variations of proviral HIV-DNA load on conditions of sustained pVL undetectability. Two different sub-studies of a multicentre prospective randomized controlled trial which compared two first-line HAART (i.e., zidovudine+lamivudine+lopinavir/ritonavir versus tenofovir+lamivudine+ efavirenz). Only patients enrolled at the coordinating centre (University of Brescia) were included in the two sub-studies. In the first substudy, we calculated pVL decrease with respect to baseline at any of the following time-points: days 1, 3, 7, 14 and 28. Decreases of the pVL were compared between the two treatment groups. In the second sub-study, we analyzed variation of proviral HIV-DNA load in CD4+ T-cells from baseline to week 52 only in patients who maintained the same treatment regimen and had sustained undetectable pVL. In either studies, linear regression analysis was used to investigate what factors could influence variations of pVL and of proviral HIV-DNA load. (i) 64 patients were studied. A significant decrease of pVL was found from day 3 on, without statistically significant differences between the two study groups. However, after adjusting for possible confounders, tenofovir+lamivudine+efavirenz resulted to be associated with greater pVL decreases. (ii) 45 patients were studied. Mean proviral HIV-DNA load decreased from 1,610 (95%CI: 879-2,341) to 896 (95% CI 499-1,293) copies/106 cells (P=0.05). Linear regression analysis showed that the decrease of proviral DNA load during follow-up was independently and inversely correlated with age. Further studies are needed to compare pVL decay between antiretroviral regimens and assess whether proviral HIV-DNA load is a surrogate marker of treatment effectiveness.

The immunopathogenic factor programmed cell death 1 (PD-1) was compared to CD38 and HIV RNA in predicting actual CD4+ T cell loss rate indicative for clinical progression. This cross sectional exploratory study included 50 consecutive, healthy HIV-infected patients off antiretroviral therapy (ART); 43 had the required observation times > 12 months. PD-1 and CD38 were determined on various T cell subsets by FACS analyses in fresh and later in parallel cryopreserved samples. Here more rapid progressors were relatively defined by having CD4 loss rates

Coronary artery disease (CAD) is an emerging complication in HIV-infected patients treated with highly active antiretroviral therapy. Immediate results and long-term outcome after coronary artery bypass graft (CABG) have not been yet evaluated in this population. Between January 1997 and December 2005, we compared baseline characteristics, immediate results and clinical outcome [Major Adverse Cardiac Events (MACE): death for cardiac cause, myocardial infarction (MI), coronary revascularization] at 41 months in 27 consecutive HIV-infected (HIV+) patients and 54 HIVuninfected (HIV-) controls matched for age and gender (mean age of the cohort, 49±8 years; 96% male) who underwent CABG. Cardiovascular risk factors were well-balanced and nearly identical in both groups. In HIV+ group, mean preoperative CD4 was 502±192/mm3 compared with 426.2±152.6/mm3 postoperatively (p=0.004) without clinical manifestations at follow-up. At 30-day, the rate of post-operative death, MI, stroke, mediastinitis, re-intervention was identical in both groups. At follow-up [median: 41-months (range: 34-60)], rate of occurrence of 1st MACE was higher in HIV+ group compared with HIV- group (11, 42% versus 13, 25%, p±0.03), mostly due to the need of repeated revascularization using percutaneous coronary intervention of the native coronary arteries but not of the grafts in the HIV+ group [9 (35%) versus 6 (11%), p±0.02]. CABG is a feasible and safe revascularization procedure in HIV+ patients with multivessel CAD. Immediate postoperative outcome was similar compared to controls. However, long-term followup was significantly different, due to an increased rate of repeated revascularization procedure in the native coronary arteries of HIV+ patients.

Nevirapine (NVP) is commonly used as a component of first-line antiretroviral therapy in resource-limited countries. We aimed to determine the risk factors for NVP-associated rash among HIV-infected patients who were initiated NVP at low CD4 cell counts in a resource-limited setting. A case-control study was conducted in HIV-infected patients who developed rash after taking NVP (case) and those who did not have rash (control). A total of 357 patients with a mean (SD) age of 36.4 (7.5) years and 52.1%male were included in the study. Mean body weight (SD) was 55.5 (10.5) kg. Of all, 179 (49.0%) patients had a history of AIDS-defining illness and 57 (16.0%) patients had history of drug allergy. Median (IQR) CD4 cell counts at the time of NVP initiation was 95 (31-226) cells/mm3. There were 115 patients in case group and 242 patients in control group. In case group, 43.0%, 54.4%, and 2.6% of patients developed grade 2, 3, and 4 of rash, respectively. Median time to develop rash was 12 (95%CI, 10.5-13.5) days. By logistic regression, history of drug allergy (OR, 3.41; 95%CI, 1.79-6.52), body weight (OR, 1.22 per each 5 kg decrement; 95%CI, 1.08-1.38), CD4 cells counts (OR, 1.20 per each 50 cells/mm3 increment; 95%CI, 1.12-1.30), and AIDS-defining illness (OR, 0.42; 95%CI, 0.25-0.70) were significantly associated with rash. In resource-limited settings where patients were initiated NVP at low CD4 cell counts, history of drug allergy, lower body weight, and higher CD4 cell count are the risk factors for NVP-associated rash. Initiation of NVP in patients with these risks needs closed monitoring.

HIV infected patients treated with highly active antiretroviral therapy (HAART) may be at increased risk of cardiovascular events, particularly if based upon the use of protease inhibitors (PI). We investigated the haemostatic markers of cardiovascular risk in 115 HIV infected subjects, divided into four groups: 1) patients naive to antiretroviral therapy (Naive; n=34 patients), or subjects that had been on a stable combination therapy for ≥12 months with either: 2) double reverse transcriptase nucleoside analogue inhibitors therapy (2NRTI; n=26), 3) 2NRTI backbone plus a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI; n=27), and 4) on a PI based regimen (PI; n=28). Forty-four healthy subjects were included as controls. Naive as well as 2NRTI and NNRTI differed from controls for higher F1+2 (P<.0001) and FVII (P<.007) levels. When comparing PI patients with controls we observed significantly higher levels of Fbg (P=.035), FVII (P<.0001), TM (P<.0089), vWF (P=.009), and F1+2 (P<.0001). The only difference observed among the 4 groups of HIV infected patients was a significantly lower level of F1+2 in PI as compared with NNRTI patients (P=.05) At least one abnormal result was observed in ≥ 90.6% of HIV infects groups, vs 43.2% of controls (P<.0001 in all cases). In conclusion, a) HIV infection per se may alter the haemostatic markers of cardiovascular risk, b) minor differences were observed among the different classes of HIV infected patients, namely between NNRTI and PI treated patients.

Objective: To analyze the factors associated with survival and to describe the specific causes of death in a large cohort of individuals with Acquired Immune Deficiency Syndrome (AIDS) in the Highly Active Antiretroviral Therapy (HAART) era. Methods: Subjects over 13 years old recorded in the AIDS registry of Barcelona and diagnosed between 1997-2005 were included. Survival analysis was performed. Causes of death were classified as being HIV-related or non- HIV-related. Results: A total of 1,759 cases were analyzed, 640 (36.3%) of them died during the follow-up. The cumulative probability of survival at five years was of 64% (95% C.I. 62%-67%). The cause of death was non-HIV-related in 28.9% of the cases, among which the most frequent were cancers (20.8%) and liver diseases (18.8%). Conclusion: An increase in the proportion of non-HIV-related deaths has been observed compared to that in the pre-HAART era. The case management of HIV-infected people must be re-directed to influence the risk factors associated with these increasing causes of death.

Objective was to assess dietary intake and physical activity in a Canadian population sample of male patients with HIV and metabolic abnormalities and to compare the data to Canadian recommendations. Sixty-five HIV-infected men with at least one feature associated with the metabolic syndrome (insulin resistance, dyslipidemia, central obesity, or lipodystrophy) were enrolled. Results from 7-day food records and activity logs were compared to the Dietary Reference Intakes and recommendations of Canada's Physical Activity Guide, respectively. Anthropometric data were also measured. Fifty-two percent of the subjects were overweight, another 15% were obese. However, energy intake (mean±SEM) (2153±99 kcal/d) was lower than the estimated requirement (2854±62 kcal/d; p<0.0001), and 84.5% of the patients reached the recommended minimum of 60 min of mild or 30 min of moderate daily exercise. Intake was adequate for protein, but high for fat and cholesterol in 40% of patients. No patient reached the recommendation for fiber. Intake from diet alone was suboptimal for most micronutrients. Prevalence was highest for low vitamin E (91% of patients) and magnesium (68%) intake, and high sodium intake (72%). In summary, a large proportion of HIV patients with metabolic abnormalities were overweight or obese. However, this was not associated with high energy intake, or reduced physical activity. High fat, low fiber and inadequate micronutrient intakes were prevalent.