The enduring tale of T cells in HIV immunopathogenesis.

HIV continues to be a major health problem worldwide even today. Owing to the intricate nature of its interactions with the immune system, HIV has remained an enigma that cleverly utilizes the host machinery to survive. Its ability to evade the host immune system, at both levels, innate and adaptive, allows the pathogen to replicate and transmit from one host to another. It has been shown that HIV has multipronged effects especially on the adaptive immunity, with CD4+ T cells being the worst affected T cell populations. Various analyses have revealed that the exposure to HIV results in clonal expansion and excessive activation of the immune system. Also, an abnormal process of differentiation has been observed suggestive of an alteration and blocks in the maturation of various T cell subsets. Additionally, HIV has shown to accelerate immunosenescence and exhaustion of the overtly activated T cells. Apart from causing phenotypic changes, HIV has adverse effects on the functional aspect of the immune system, with evidences implicating it in the loss of the capacity of T cells to secrete various antiviral cytokines and chemokines. However, there continues to be many aspects of the immunopathogenesis of HIV that are still unknown and thus require further research to convert the malaise of HIV into a manageable epidemic.

Genomic architecture of HIV-1 infection: Current status & challenges.

Studies on host genomics have revealed the existence of identifiable HIV-1 specific protective factors among infected individuals who remain naturally resistant viraemia controllers with little or no evidence of virus replication. These factors are broadly grouped into those that are immune associated (MHC, chemokines, cytokines, CTLs and others), linked to viral entry (chemokine co-receptors and ligands), act as post-entry restriction elements (TRIM5a, APOBEC3) and those associated with viral replication (cytokines and others). These features have been identified through multiple experimental approaches ranging from candidate gene approaches, genome wide association studies (GWAS), expression analysis in conjunction with functional assays in humans to primate based models. Several studies have highlighted the individual and population level gross differences both in the viral clade sequences as well as host determined genetic associations. This review collates current information on studies involving major histocompatibility complex (MHC) as well as non MHC genes in the context of HIV-1 infection and AIDS involving varied ethnic groups. Special focus of the review is on the genetic studies carried out on the Indian population. Further challenges with regard to therapeutic interventions based on current knowledge have been discussed along with discussion on documented cases of stem cell therapy and very early highly active antiretroviral therapy (HAART) interventions.

Loss of CD127 & increased immunosenescence of T cell subsets in HIV infected individuals.

Background & objectives: HIV infection is characterized by a perturbation in T cell homeostasis, leading to alteration in T cell subsets. In addition to alteration in differentiation, HIV infection also leads to change in T cell survival and regenerative capacity, as suggested by differential expression of CD127 and CD57. We evaluated the expression patterns of CD127 and CD57 on CD4 and CD8 effector, memory and naïve T cell subsets in HIV-infected and uninfected individuals. Methods: We characterized T cell subsets based on expression of these markers, and compared their expression pattern in HIV infected subjects and uninfected controls. We further assessed therapy generated changes in these subsets and expression of CD127 and CD57 on them. Results: There was a generalized decrease in naïve CD4 and CD8 T cells in HIV infected subjects. These changes in T cell subset distribution were related to antigen load. CD127 expression was significantly reduced in T cells from HIV infected subject. In association to this, HIV infected subjects had higher percentage of T cell subsets expressing CD57. Increased CD57 and reduced CD127 expression correlated with plasma viraemia and CD8 T cell activation state. Incomplete restoration of T cell subset proportions was observed, despite suppression of viral replication and increase in CD4 T cell counts. Further, the improvement was more pronounced in CD127 expression. Interpretation & conclusions: HIV infected subjects have reduced T cell regenerative capacity along with increased senescence, highlighting decreased proliferation and effector activities.

Genital mycoplasma & Chlamydia trachomatis infections in treatment naïve HIV-1 infected adults.

Background & objectives: Sexually transmitted infections (STIs) enhance the transmission of human immunodeficiency virus (HIV). Thus, screening for STIs is a routine component of primary HIV care. There are limited data for selective screening guidelines for genital mycoplasmas and Chlamydia trachomatis in HIV-infected adults. The aim of the present study was to determine the frequency of genital infections with Ureaplasma spp., Mycoplasma hominis, M. genitalium and C. trachomatis in treatment naïve asymptomatic HIV-1 - infected adults and study their association with CD4+ T-cell count. Methods: First-void urine samples were collected from 100 treatment-naïve HIV-1-infected adults and 50 healthy volunteers. C. trachomatis and M. genitalium were detected by polymerase chain reaction (PCR). Ureaplasma spp. and M. hominis were detected by both culture and PCR. Circulating CD4+ cell counts of HIV-1-infected patients were determined from peripheral blood by flow-cytometry. Results: C. trachomatis was detected in 7 per cent of HIV-1-infected adults compared to none in control population. Ureaplasma spp. and M. hominis showed infection rates of 6 and 1 per cent in the HIV group and 2 and 0 per cent in the control group, respectively. None of the individuals from the patient and control groups was tested positive for M. genitalium. A significant association was found between CD4 cell count and detection of C. trachomatis in HIV-infected adults (P = 0.01). Interpretation & conclusions: Screening of HIV-infected individuals for C. trachomatis infection could be recommended as a routine component of HIV care. The role of mycoplasmas as co-pathogens of the genitourinary tract in HIV-1 infected patients seems to be unlikely. Further longitudinal studies need to be done to confirm these findings.

Current practices in laboratory monitoring of HIV infection.

After a diagnosis of HIV infection is made, the patient needs to be monitored using both clinical assessment and laboratory markers. HIV/AIDS monitoring is essential in guiding when to recommend initiation of therapy. Clinical monitoring will include staging of the HIV/AIDS disease using either the presence or absence of HIV-related signs and symptoms using the WHO staging system. Various laboratory methods can be used to monitor the disease progression and to guide whether the patient will need antiretroviral therapy or not. Laboratory monitoring for patients who are not on drugs is done to provide information about the stage of illness; to enable the clinician to make decisions on treatment and to give information on prognosis of the patient. Patients on drugs are monitored to assess their response to treatment with antiretroviral drugs and to detect any possible toxicity and improvement associated with the antiretroviral drugs.

Usefulness of hemoglobin and albumin as prognostic markers for highly active antiretroviral therapy for HIV-1 infection.

Background: Usefulness of hemoglobin and albumin as prognostic markers for highly active anti-retroviral therapy for HIV-1 infection. Introduction: Anemia and hypoalbuminemia are common complications in human immunodeficiency virus (HIV) infection. We aimed to investigate the changes in hemoglobin and albumin levels in response to highly active antiretroviral therapy (HAART). Further, we evaluated the appropriateness of using hemoglobin and albumin as HIV disease progression markers. Materials and Methods: A prospective longitudinal study of 122 subjects was carried out. Pre-treatment, one year, and two year post-treatment hemoglobin, and albumin levels were correlated with respective CD4+ T cell counts. The sensitivity, specificity, and positive predictive value of each marker against CD4+ T cell counts were calculated in order to establish the appropriateness of use of these parameters as surrogate disease progression and prognostic markers. Results: Mean hemoglobin and albumin levels pre-, one, and two year post HAART were 9.7 g/dL, 12.1 g/dL, and 13.1 g/dL, respectively, P = 0.001; albumin: 3.7 gm%, 4.4 gm%, and 4.7 gm%, respectively, P = 0.001. There was a positive correlation between hemoglobin, albumin, and CD4+ T cell count at pre-treatment, one year, and two year post-treatment visit. Both albumin and hemoglobin had high sensitivity when compared to CD4+ T cell counts. Conclusions: Hemoglobin and albumin levels were found to increase after initiation of HAART. Hemoglobin and albumin were seen to be a strong prognostic marker of HIV disease progression at pre-, one, and two year post-treatment. Therefore, hemoglobin and albumin may be used together along with CD4 + T cell counts in HIV management, particularly in resource-poor settings.

Defects in blood dendritic cell subsets in HIV-1 subtype C infected Indians.

Background & objective: DCs trigger both innate and adaptive immune responses to control HIV infection and represent a viral reservoir acting as target and HIV carriers for infection of permissive CD4+ T-cells. DCs thus form a very attractive study subject to further our existing knowledge of HIV induced immunopathogenesis due to its diverse and crucial role in HIV infection establishment, viral dissemination, immune evasion, viral persistence, etc. We aimed to characterize the effect of HIV infection on myeloid and plasmacytoid dendritic cell subsets in a group of HIV-1 subtype C infected treated or untreated Indian individuals. Methods: Blood DC subset numbers and immunophenotype were studied for 79 HIV infected subjects at various stages of disease and compared with 13 HIV-uninfected controls. Comparisons were also made between groups of subjects based on their CD4+ T cell counts and also experience of antiretrovirals. Results: Significant decreases were observed in blood DC counts and the two DC subsets in HIV infected individuals. Subjects with lowest CD4+ T cell counts also had a drastically reduced DC subset pool which correlated positively with plasma viraemia and negatively with CD4+ T cell counts. DC subsets from HIV infected subjects showed higher expression of co-stimulatory molecules CD40 and CD86, and HIV-1 co-receptors CXCR4 and CCR5 which correlated positively with HIV-1 plasma viraemia. The alterations in blood DCs were partly resolved in ART receiving study subjects. Interpretation & conclusions: Correlation between DC subset activation state and viraemia supports the role of DC activation on viral replication and CD4+ T cell depletion.

Multidimensional health status of HIV-infected outpatients at a tertiary care center in north India.

Background : Quality of life (QOL) scores inform researchers acquainted with such tools about patients' perception of various domains of their health. The scores provide a useful denominator for clinical trials, especially in chronic diseases with therapeutic side effects, such as HIV. However, in clinical settings, there is a felt need of description of problems commonly perceived by patients. Aim : This study describes the multidimensional health-related issues of HIV-positive patients. Settings and Design : Cross-sectional design with convenient sampling was used to recruit 138 HIV-positive patients at the outpatient section of the Department of Medicine of a tertiary care hospital in north India. Materials and Methods : A structured questionnaire was used to collect information about health-related problems. Identified problems were assessed using a Likert scale for severity. Results : Out of the 20 assessed problems, the patients reported positive for an average of 12.01 +/- 3.78 problems. The most prevalent problems were those related to emotions (98.6%), lack of energy (96.4%), and health perception (92.0%). The most distressing problems were 'feeling that health was not good' (77.5%) and 'health was bad' (75.4%). The number of problems reported was significantly related to weight loss ( P = 0.006) and clinical category ( P = 0.023). A significant correlation was observed between weight loss and problems in social activities ( P P P P = 0.002).Conclusion : Many patients have significant problems in dimensions other than physical. A physician's awareness about these problems is important for a holistic patient management.

Antiretroviral treatment in resource-poor settings: a view from India.

CONTEXT: The introduction of highly effective generic antiretroviral drugs at reduced cost has transformed the face of HIV/AIDS epidemic in developing countries like India. However, there is an urgent emphasis on developing and implementing guidelines for antiretroviral treatment monitoring by laboratory methods utilizing the available technologies in resource-limited settings. AIM: We studied the efficacy of antiretroviral treatment, adherence to therapy and motivation of patients for regular treatment monitoring by CD4 counts. SETTINGS AND DESIGN: A longitudinal cohort study on an established cohort of 166 HIV-1-infected Indian individuals. MATERIALS AND METHODS: Study subjects were followed up for the period from January 2002 to November 2006. Their clinical status and treatment regimen were recorded and CD4 counts were performed at each visit. STATISTICAL ANALYSIS: Repeated-measures ANOVA was used to compute changes in median CD4 counts at each visit in the different treatment groups. RESULTS: We observed a growing awareness and motivation for regular HIV disease monitoring among patients, accompanied by a trend of increasing median CD4 counts at all subsequent follow-up visits after initiation of antiretroviral treatment. CONCLUSIONS: The study gives an insight into the institutional efforts for the establishment of cohorts for longitudinal studies, which will help in designing effective treatment guidelines, thus providing impetus to the free public sector antiretroviral therapy program in India. Such formative research aims to fill the lacunae in the limited available data for the formulation of treatment-monitoring guidelines in resource-poor settings of developing countries like India.

Polymicrobial keratitis in an HIV-positive patient.

We describe a case with non-responding polymicrobial spontaneous corneal ulceration in an HIV-positive patient. Acanthamoeba was among the microorganisms isolated.