Current HIV Research - Volume 6, Issue 6, 2008

Oral candidosis (syn. Oral candidiasis; OC), is a collective term given to a group of oral mucosal disorders caused by the fugal pathogen belonging to the genus Candida. The association of OC with the human immunodeficiency virus (HIV) infection has been known since the advent of the acquired immune deficiency syndrome (AIDS) pandemic. OC is one of the earliest manifestations of HIV disease in high risk individuals not undergoing chemotherapy and is also a strong predictor of the subsequent risk of AIDS-related illness or death. With the advances in HIV therapy, such as highly active anti-retroviral therapy (HAART), the prevalence and presenting features of OC have changed in HIV-infected individuals, especially those in industrialized countries. The presence of OC in “controlled” HIV-positive individuals may be indicative of a patient nonadherence to therapy or possible failure. The factors contributing to the genesis of OC and its progression in these individuals are poorly understood, but may include an interrelationship between HIV and Candida and/or a dysfunction in the local immunity, superimposed on weakened cell-mediated immunity and depletion of CD4 T cells. The dramatic increase in publications on this topic matches the increased importance and awareness of this opportunistic infection in HIV-infected individuals. In this review we first address the epidemiologic and clinical features of OC in HIV-infected persons, followed by the current understanding of the pathogenesis of OC in the context of HIV infection with a concluding section on the current management concepts of OC.

The major etiologic agent of the acquired immunodeficiency syndrome (AIDS) is the human immunodeficiency virus type 1 (HIV-1), which belongs to the family of human retroviruses. This pandemic infection affects millions of people worldwide. The most efficient current treatment regimen for HIV-infected individuals combines two or more drugs targeting different HIV-specific enzymes. However, the emergence of multiple drug-resistant HIV-1 strains and the side effects of drug-based therapies make alternative approaches for the treatment of HIV infection and AIDS necessary. RNA-based antiviral approaches are among the most promising for developing long-term anti-HIV therapies. Anti-HIV-1 RNA-based strategies include ribozymes, antisense RNAs, RNA aptamers, RNA decoys, external guide sequences (EGS) for site-specific cleavage of RNA molecules with human ribonuclease P (RNase P), modified small nuclear RNA (RNAu) and small interfering RNAs (siRNAs). This review describes the main features and functions of viral and cellular targets as well as the different classes of RNA molecules that have been explored in developing therapeutic strategies against HIV infection. Many RNA-based strategies are already being tested in human clinical trials or are currently being developed for future trials.

Simple antibodies or vector-induced T cell immunity are unable to provide broad immunity to HIV. Although broadly reactive neutralising antibodies are a goal of vaccination, this remains elusive. There is growing evidence that HIV-specific antibodies that mediate their activity via the Fc-receptor, such as antibody dependent cellular cytotoxicity (ADCC), have an important role in controlling HIV infection. Newer assays are being developed that enable HIV-specific ADCC responses to be finely mapped. In turn, this should allow a more definitive analysis of the effectiveness of HIVspecific ADCC antibodies. However, progressive dysfunction of effector cells that mediate ADCC responses, such as NK cells, combined with immune escape variants that emerge from effective ADCC responses, likely undermine the utility of ADCC responses during chronic HIV infection. Nonetheless the utility of ADCC responses in preventing HIV infection requires urgent consideration.

The oral and esophageal mucosa have been identified as possible sites of HIV/SIV entry following oral infection. Here, gamma/delta (γδ) T cells, a multi-functional T cell subset, were assessed at oral/esophageal mucosa and lymphoid sites at the earliest times (1-14 days) post-oral SIV inoculation utilizing quantitative RT-PCR. During these earliest times post-infection, decreased γδ TCR mRNA levels were observed at the oral gingiva and esophageal mucosa, while increased levels were observed within regional lymph nodes (cervical and retropharyngeal). Higher lymph node γδ TCR levels were associated with increased mRNA expression of the lymphoid homing chemokine/receptor (CCL21/CCR7) pair in these lymph nodes. In contrast to γδ TCR levels, CD4 mRNA expression remained relatively stable through 4 days post-infection, and depletion of CD4 T cells was only evident after 7 or 14 days post-infection. The decrease of γδ T cell mRNA from mucosal sites and the corresponding increase at lymphoid sites suggest a rapid redistribution of these immune cells at these earliest times post-SIV infection.

Protection against HIV-1 infection in exposed seronegative (ESN) individuals likely involves natural resistance mechanisms that have not been fully elucidated. Human beta defensins (HBD) are antimicrobial peptides found primarily in mucosae, the main ports of HIV entry. HBD-2 and 3 mRNA are induced by HIV-1 in human oral epithelial cells and exhibit strong anti-HIV-1 activity; in addition, polymorphisms in the DEFB1 gene, which encodes HBD-1, have been associated with resistance/susceptibility to different infections, including HIV-1. Here, we have assessed the association of HBD expression with the ESN phenotype. Peripheral blood and vaginal/endocervical and oral mucosal samples were taken from 47 ESN, 44 seropositive (SP) and 39 healthy controls (HC). HBD-1, 2 and 3 mRNA copy numbers were quantified by real time RT-PCR and A692G/G1654A/A1836G polymorphisms in the DEFB1 gene were detected by restriction fragment length polymorphisms and confirmed by nucleotide sequencing. ESN expressed significantly greater mRNA copy numbers of HBD-2 and 3 in oral mucosa than HC; p=0.0002 and p=0.007, respectively. mRNA copy numbers of HBD-1, 2 and 3 in vaginal/endocervical mucosa from ESN and HC were similar. Homozygosity for the A692G polymorphism was significantly more frequent in ESN (0.39) than in SP (0.05) (p=0.0002). In summary, ESN exhibited enhanced mucosal expression of the innate defense genes HBD-2 and 3; however, additional studies are required to verify these results and the potential association of the A692G polymorphism to the relative resistance of ESN to HIV-1 infection.

Chemokines receptors are used by HIV-1 for entry into CD4+ T cells. The β-chemokines are capable of inhibiting HIV replication. This study determined the CCR5 and CXCR4 expression on T cells in HIV-1-infected patients treated with HAART. The successfully treated group (plasma viral load <400 copies/mL), when compared with the failure group (plasma viral load >400 copies/mL), had higher median CD4+ T cells count (583 and 245 cells/mm3; respectively, p< 0.0001). The failure patients had higher numbers and intensity of CCR5 and CXCR4-expressing T cells. Successfully treated patients were able to normalize the co-receptors expression-over on T cells. The viremic group showed higher CCR5 expression on CD4+ T cells and lower number of cells; CCR5 expression was normalized in the aviremic group; the naive group showed lower CCR5 expression and higher numbers of CD4 T cells; all groups showed normal CXCR4 expression compared to healthy controls. These findings may have clinical implications, since down-regulation of these co-receptors could be an adjuvant strategy for anti-HIV treatment.

It has long been recognized that drug metabolism and drug toxicity may vary greatly between individuals, affecting both efficacy and toxicity. Pharmacogenetics could benefit HIV therapeutics because of the high prevalence of drug-related adverse events and the long term nature and complexity of combination therapy. In recent years a number of associations between human genetic variants and predisposition to drug toxicity and risk of virologic failure have been described. This review summarizes the existing literature on pharmacogenetic determinants of antiretroviral drug exposure, toxicity, and activity. Studies across the world have consistently demonstrated that HLA-B*5701 predicts the likelihood of hypersensitivity reactions to abacavir. As a consequence, pharmacogenetic screening for HLA-B*5701 has entered routine clinical practice and is recommended in most guidelines before starting an abacavir containing regimen. Moreover, prospective clinical trials and cohort studies have identified a number of associations between human genetic variants, drug metabolism and toxicity. These include nevirapine hypersensitivity and hepatotoxicity, efavirenz plasma levels and central nervous system side effects, indinavir- and atazanavir-associated hyperbilirubinemia, antiretroviral drug-associated peripheral neuropathy, lipodystrophy and hyperlipidaemia, NRTI-related pancreatitis, and tenofovir-associated renal proximal tubulopathy. Thus, pharmacogenetics is expected to play an important role in HIV treatment in the near future. The aim of the present paper is to provide HIV clinicians with a comprehensive review of recent achievements and future prospects for HIV pharmacogenetics.

Antiretroviral therapy in human immunodeficiency virus infection is occasionally associated with poor immunologic responses despite full suppression of viral replication. As some combinations of nucleoside analogues (NA) have been associated with paradoxical depletion of CD4+ T- cells, we postulated that depleting the antiretroviral regimen of NAs would improve quantitative immunological parameters. In a longitudinal prospective study we quantified CD4+ Tcells after removing NAs from antiretroviral therapy. The NA for regimen consisted of atazanavir (300mg qd), saquinavir (1000mg bid), and ritonavir (100mg qd) in 14 patients with immunologic failure despite undetectable plasma HIV-RNA (CD4+ T-cells < 250 cells/μL (<17%) HIV RNA, <= 50 copies/mL). Additionally, we assessed the state of immunologic activation markers (CD38+HLA-DR+ on CD4+ and CD8+ T-cells) by flow cytometry. The regimen was well tolerated. During the 48 week study CD4+ T-cell counts improved significantly (mean and ± SEM [standard error of mean], baseline: 174/μL (12.4%) [15, 5.8%], week 24: 232/μL (14%) [26, 5.3%], week 48: 267/μL (15.4%) [34, 4.3%]) with preservation of full viral suppression (p<0.05). Activation parameters of CD4+ T-cells, but not of CD8+ T-cells, decreased significantly. This treatment strategy may represent an option for patients with poor immunologic responses to antiretroviral therapy despite undetectable viremia.

We describe the case of a young HIV-positive man on effective HAART with excellent viro-immunological control who presented a massive cardiac infarction. Despite the presence of clinical risk factors for cardiovascular disease, the patient had normal arterial carotid IMT values, known to be strong predictors of atherosclerosis and stroke. Interestingly, parameters of T-cell activation (CD8+CD38+) were shown to increase just before the onset of myocardial infarction. As T-cell activation is known to mediate atherosclerosis, the authors suggest that surrogate immunologic markers should be identified to better assess cardiovascular risk in the setting of HIV infection.

The decentralization of pediatric HIV/AIDS-treatment programs to primary health care centers in rural Africa has lagged behind. In order to guide an analysis of current access to care, a sociological conceptual framework was developed. This framework focused on conditions of seeking pediatric HIV care among community members and initiating pediatric HIV care by primary health care workers (PHCWs). The use of the sociological conceptual framework helped in determining basic research questions and current gaps in knowledge (e.g. the effectiveness and long-term impact of Western counseling models in rural African settings), exploring the need for healthcare level specific research and policy (e.g. in infant HIV-testing), identifying potential pitfalls in decentralizing pediatric HIV treatment programs to rural African communities (e.g. lack of self-confidence in HIV counseling among PHCWs). Consequently, the use of the sociological model is helpful in maximizing efforts and resources allocated to such roll-out. A renewed appreciation for primary health care in general, however, remains crucial for a successful decentralization of pediatric HIV/AIDS-treatment programs to rural Africa.

Highly active antiretroviral therapy (HAART) including protease inhibitors (PIs) has been independently associated with an abnormal lipid profile, and recent studies have shown an increased risk of cardiovascular complications in patients with prolonged exposure to HAART. Aim of our open-label, randomized, prospective study is to evaluate the role of different statins in the management of PI-associated hypercholesterolaemia. Ninety-four adult patients on a stable PIbased antiretroviral therapy since at least 12 months, and presenting hypercholesterolaemia (total cholesterol level >250 mg/dL) of at least 3-month duration and unresponsive to a hypolipidaemic diet and physical exercise, were randomized to a hypolipidaemic treatment with rosuvastatin (10 mg once daily), pravastatin (20 mg once daily) or atorvastatin (10 mg once daily), and were followed-up for 12 months. Among the 85 subjects who completed the study, rosuvastatin was employed in 26 cases, pravastatin in 31, and atorvastatin in 28. At the close of 1-year follow-up, statins led to a mean reduction of 21.2% and 23.6% versus baseline total cholesterol and LDL cholesterol levels, respectively (p=0.002). Mean decrease in total cholesterol concentration was significantly greater with rosuvastatin (25.2%) than with pravastatin (17.6%; p=0.01) and atorvastatin (19.8%; p=0.03). During these 12 months, all administered statins showed a favourable tolerability profile, and patients' plasma HIV viral load did not present any variation. All used statins showed a significant efficacy and a good tolerability in the treatment of diet-resistant hyperlipidaemia, but rosuvastatin was found to be more effective in reducing total and LDL cholesterol levels.

We examined the impact of cognitive and biomedical variables on unprotected anal intercourse between HIV-1 infected men and casual sexual partners in a Sydney-based cohort. Participants answered questionnaires examining insertive and receptive intercourse with and without ejaculation. They completed a modified optimism-scepticism scale, a sexual beliefs scale and a clinical/demographics questionnaire. CD4 count, blood and semen VL were assessed. 43 of 109 reported anal intercourse with HIV+ partners, 33 with HIV- partners and 38 with partners of unknown status. With HIV+ partners past sexually transmittable infections were associated with receptive intercourse without ejaculation (p = 0.03) and insertive intercourse without ejaculation (p = 0.06) while sexual beliefs were associated with insertive intercourse without ejaculation (p = 0.038), receptive intercourse with ejaculation (p = 0.016) and insertive intercourse with ejaculation (p = 0.077). Sexual beliefs were found to have some association with unprotected receptive intercourse without ejaculation with HIV- partners (p = 0.071). With unknown serostatus partners, treatment-optimism (p = 0.026) had association with insertive intercourse with ejaculation while optimism (p = 0.002), sexual beliefs (p = 0.039) and recent VL (p = 0.059) had associations with insertive intercourse without ejaculation. Current STI had association with receptive intercourse with ejaculation with unknown status partners (p = 0.014). We found between-group differences in variables associated with different types of unprotected anal intercourse that may guide the development of prevention strategies.

The proportion and significance of HIV-1 infection of CD8+ T-cells was examined in a patient cohort of HIV-1 seropositive (n=28) and seronegative individuals (n=4). It was hypothesized that irrespective of the clinical status of the patients, productively HIV-1 infected CD8+ T-cells would be found and these cells would contribute to the plasma viral load in vivo. Flow cytometric analysis using fluorochrome-conjugated antibodies, RT-PCR analysis using HIV-1pol specific primers, and quantification of HIV-1 viral transcripts by ex vivo culture of isolated CD8+ T-cells were employed. In 22 of the 28 patient samples analyzed, a significantly higher proportion of cells with expression of CD8+HIV-1gag+ than of CD4+HIV-1gag+ T-cells was observed (36.9% ± 10.0% vs 26.4% ± 13.1% respectively, p< 0.01). No correlation was observed between absolute CD4 counts, CD8 counts, plasma viral load and CD8+ T cell infection. RT-PCR analysis indicated the presence of HIV-1 transcripts in the ex vivo isolated CD8+ T-cell population. Ex vivo isolated CD8+ T-cells demonstrated productive infection over time. We conclude, with three lines of evidence detecting and measuring HIV-1 infection of CD8+ T-lymphocytes, that this cellular target and reservoir may be central to HIV-1 pathogenesis.