HIV-1C and HIV-1B Tat protein polymorphism in Southern Brazil.

The transactivator of transcription (Tat) is a key HIV regulatory protein. We aimed to identify the frequency of key polymorphisms in HIV-1C compared with HIV-1B Tat protein, chiefly in the cysteine-, arginine-, and glutamine-rich domains and identify novel point mutations in HIV-1B and C sequences from Southern Brazil. This study was the first to investigate the genetic diversity and point mutations within HIV-1 Tat C in a Brazilian cohort. This was an observational, cross-sectional study, which included sequences of HIV-1B (n = 20) and HIV-1C (n = 21) from Southern Brazil. Additionally, 344 HIV-1C sequences were obtained from the Los Alamos database: 29 from Brazil and 315 from Africa, Asia, and Europe. The frequency of C31S substitution on HIV-1 Tat C in Brazil was 82% vs. 10% in the HIV-1B group (p < 0.0001). The frequency of the R57S substitution among the HIV-1C sequences from Brazil was 74% vs. 20% in HIV-1B (p = 0.004), and that of substitution Q63E in HIV-1C was 80% and 20% in HIV-1B (p < 0.0001). The mutation P60Q was more frequent in HIV-1B than in HIV-1C (55% and 6.12%, respectively, p < 0.0001)). Novel point mutations in the HIV-1C and B Tat functional domains were described. The frequency of C31S and other key point mutations in HIV-1 Tat C in Brazil were similar to those described in Africa, although lower than those in India. The Tat-B and C sequences found in Southern Brazil are consistent with biological differences and have potential implications for HIV-1 subtype pathogenesis.

Prolonged Posttreatment Virologic Control and Complete Seroreversion After Advanced Human Immunodeficiency Virus-1 Infection.

BACKGROUND: Possible human immunodeficiency virus (HIV)-1 clearance has rarely been reported. In this study, we describe a unique case of an HIV-positive, combination antiretroviral therapy (cART)-experienced woman with prior acquired immunodeficiency syndrome (AIDS) who has not experienced viral rebound for over 12 years since discontinuing cART. METHODS: Leukapheresis, colonoscopy, and lymph node excision were performed for detailed examination of virologic (including HIV reservoir) and immunologic features. Comparisons were made with chronically infected patients and healthy controls. RESULTS: No HIV-specific antibodies were detected in serum. Plasma HIV ribonucleic acid (RNA) levels were <0.2 copies/mL, and, except for low-frequency HIV deoxyribonucleic acid (DNA)+ cells in lymph node tissue (1 copy/3 × 106 cells), HIV antigen could not be detected by quantitative virus outgrowth (<0.0025 infectious units/106 CD4+ T cells) or by most measurements of HIV RNA or DNA in blood, lymph node, or gut-associated mononuclear cells. Human immunodeficiency virus-specific T-cell responses were detectable but low. Brain imaging revealed a prior biopsy site and persistent white matter disease since 1996. Human immunodeficiency virus DNA+ cells in the 1996 brain biopsy specimen confirmed her identity and initial HIV diagnosis. CONCLUSIONS: This represents the first report of complete seroreversion, prolonged posttreatment virus suppression, a profoundly small HIV reservoir, and persistent HIV-specific T cells in an adult with prior AIDS.

Parasitic Infections of the Nervous System.

Parasitic infections of the central nervous system are much more common than suspected, although most infections are asymptomatic. For example, parasites like the ubiquitous protozoa Toxoplasma gondii or the nematode larvae Toxocara canis infect significant proportions of the human population. Other parasitic infections such as malaria and neurocysticercosis are widespread in developing countries and become major causes of neurological morbidity in these regions as well in immigrants and travelers. This article reviews parasitic pathogens causing neurological morbidity and mortality, including an extensive list of less common parasitic infections of the human nervous system.

Soluble and cell-associated insulin receptor dysfunction correlates with severity of HAND in HIV-infected women.

BACKGROUND: Blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND). These abnormalities may occur as a result of chronic HIV infection, long-term use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population. OBJECTIVE: To determine if changes in soluble and cell-associated insulin receptor (IR) levels, IR substrate-1 (IRS-1) levels, and IRS-1 tyrosine phosphorylation are associated with the presence and severity of HAND in a cohort of HIV-seropositive women. METHODS AND RESULTS: This is a retrospective cross-sectional study using patient database information and stored samples from 34 HIV-seropositive women and 10 controls without history of diabetes from the Hispanic-Latino Longitudinal Cohort of Women. Soluble IR subunits [sIR, ectodomain (α) and full-length or intact (αß)] were assayed in plasma and CSF samples by ELISA. Membrane IR levels, IRS-1 levels, and IRS-1 tyrosine phosphorylation were analyzed in CSF white cell pellets (WCP) using flow cytometry. HIV-seropositive women had significantly increased levels of intact or full-length sIR in plasma (p<0.001) and CSF (p<0.005) relative to controls. Stratified by HAND, increased levels of full-length sIR in plasma were associated with the presence (p<0.001) and severity (p<0.005) of HAND. A significant decrease in IRS-1 tyrosine-phosphorylation in the WCP was also associated with the presence (p<0.02) and severity (p<0.02) of HAND. CONCLUSIONS: This study provides evidence that IR secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women. Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND.

Associations of cigarette smoking with viral immune and cognitive function in human immunodeficiency virus-seropositive women.

Cigarette smoking alters the immune system and may improve cognitive deficits in neuropsychiatric disorders. Smoking prevalence is high in human immunodeficiency virus (HIV)-infected patients; however, its effect on HIV-associated cognitive impairment remains unknown in the era of antiretroviral treatment. The authors examined associations of smoking with viral immune profile and cognitive function in a cohort of HIV-seropositive women. This observational cross-sectional study included 56 women (36 HIV-seropositive and 20 HIV-seronegative) surveyed with a tobacco questionnaire: the Fagerström Test for Nicotine Dependency. Viral immune status was obtained 6 to 12 months before questioned. Neurocognitive testing (NP) assessed verbal memory, frontal/executive function, psychomotor speed, and motor speed. A reference group of HIV-seronegative women was used to calculate standardized z-scores. Cognitive impairment was classified using a modified American Academy of Neurology criteria, adding an asymptomatic group based on NP tests. Statistics included parametric and nonparametric tests. HIV-seropositive women were more likely to report a history of smoking (P = 0.028). Among them, current smoking correlated with higher plasma viral load (P = 0.048), and history of smoking correlated with lower CD4 cell count (P = 0.027). The authors observed no associations between cognitive impairment and either current or past history of smoking and no differences in neurocognitive domain scores between HIV-seropositive and -seronegative women or between those with and without a history of smoking. However, restricting analysis to HIV-seropositives showed a significant better performance on the frontal/executive domain in those with history of smoking. In summary, history of smoking correlated with better frontal/executive cognitive domain performance in HIV-seropositive women and with worse viral immune profile.

Challenges to the diagnosis and management of HIV dementia.

Although it has been evident since the early days of the HIV epidemic that a dementing illness often accompanies HIV infection and that the virus invades the nervous system soon after systemic infection, the clinical syndrome has evolved with the introduction of antiretroviral therapy. Milder forms of cognitive impairment with a variable course, evident at higher CD4+ cell counts, are now more frequently seen. Furthermore, these patients often have other comorbidities such as drug abuse, hepatitis C virus infection, depression, and those associated with aging as confounding factors. The antiretroviral drugs may themselves be toxic or cause an immune reconstitution syndrome that needs to be distinguished from HIV dementia. The treating physician thus faces several new challenges in the diagnosis and treatment of a patient with HIV infection who presents with cognitive impairment. In this article, we provide a systematic approach to addressing each of these issues and guidelines for management of these patients. We also discuss the latest experimental approaches and the clinical trials being conducted for the better management of this population.

Prevalence of human immunodeficiency virus-associated cognitive impairment in a group of Hispanic women at risk for neurological impairment.

Human immunodeficiency virus (HIV)-associated cognitive impairment, a significant cause of morbidity, affects up to 30% of HIV-infected people. Its prevalence doubled as patients began to live longer after the introduction of highly active retroviral therapy. Women are now one of the fastest growing groups with acquired immunodeficiency syndrome (AIDS) in the United States and Puerto Rico, but relatively little is known about the prevalence and characteristics of cognitive dysfunction in HIV-infected women. In this study the authors investigated its prevalence in a group of HIV-1-seropositive Hispanic women in Puerto Rico. Forty-nine women with a nadir CD4 cell count of < or = 500 cells/mm3 were enrolled. Cognitive impairment was defined according to the American Academy of Neurology criteria for HIV dementia as modified to identify an "asymptomatic cognitively impaired" group. Observed prevalence was compared with prevalence in other populations in United States, Europe, and Australia. Differences in clinical markers and neuropsychological test performance among the cohort stratified by cognitive impairment were tested. Cognitive impairment was observed in 77.6% (38/49) of cases; asymptomatic cognitive impairment in 32.7% (16/49); minor cognitive motor disorders in 16.3% (8/49); and HIV-associated dementia (HAD) in 28.6% (14/49). Cognitive impairment did not correlate with age, CD4 cell count, viral load, or treatment modality. The cross-sectional prevalence of HIV-associated cognitive impairment was 77.6% (28.6% for HAD). These findings should enhance awareness of the prevalence of HIV-associated cognitive impairment, both clinically apparent and "asymptomatic," in Hispanic women and lead to improvements in areas such as education and compliance and to reevaluation of treatment interventions.