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Current HIV research [journal]
- HIV Infection, Antiretroviral Therapy Initiation and Longitudinal Changes in Biomarkers of Organ Function. [Journal Article]
- Curr HIV Res 2014; 12(1):50-9.
Background:HIV is associated with end-organ diseases of aging via unclear mechanisms. Longitudinally assessing how HIV infection and ART initiation affect biomarkers of end organ function/disease could clarify these mechanisms. We investigated longitudinal changes in clinical biomarkers following 1) HIV infection and 2) ART initiation with evidence of viral suppression.
Methods:Cohort: Veterans Aging Cohort Study Virtual Cohort (VACS VC). VACS VC is a longitudinal cohort of HIV infected (HIV+) and race-ethnicity, sex, age, and clinical site-matched uninfected Veterans enrolled in the same calendar year. Inclusion criteria: a negative and successively positive (>six months) HIV antibody test. We used Wilcoxon signedrank tests to analyze 1) the effect of HIV infection on lipids, renal, hepatic and hematologic/cardiovascular biomarkers and 2)whether ART initiation with HIV-1 RNA<500 cpm reverts any changes back to pre-HIV levels.
Results:422 Veterans had at least 1 biomarker measurement available prior to HIV infection and prior to ART initiation. 297 had at least 1 biomarker measurement available prior to HIV infection and after ART initiation with evidence of viral suppression. Mean age prior to HIV infection was 43 years. HIV infection was associated with reduction in total cholesterol, HDL cholesterol, LDL cholesterol, serum albumin, ALT, platelet count, hemoglobin and elevation of FIB-4 score and triglycerides. These changes occurred without significant changes in BMI. ART initiation (with HIV-1 RNA<500cpm) did not reverse alteration in triglycerides, LDL cholesterol, hemoglobin, or FIB-4 to pre-HIV infection levels.
Conclusions:HIV infection is associated with longitudinal changes in serum levels of several biomarkers of end-organ function/disease and mortality. Multiple biomarkers (triglycerides, LDL cholesterol, hemoglobin, and FIB-4 ) remain altered from levels prior to HIV infection levels even following inititiation of ART and evidence of viral suppression. These results give insights into underlying mechanisms of increased risk for aging-related chronic diseases in the context of HIV infection.
- On the Evolution of AIDS/HIV Treatment: An Optimal Control Approach. [Journal Article]
- Curr HIV Res 2014; 12(1):1-12.
After more than 30 years of continuous research as well as unselfish efforts, tremendous and exciting developments have been achieved towards the evolution of HIV treatments both in the directions of antiretroviral therapy and effective vaccine for HIV positive patients. Recent research shows that triple-drug antiretroviral therapy can 'functionally cure' [1, 2] the HIV positive patients, which is a milestone in the therapeutic treatments of AIDS. Despite the significant progress on the evolution of AIDS/HIV treatments, it is still a curse for the humanity and until today the world's most serious epidemic as well as leading infectious killer disease. However, Millennium Development Goals (MDGs) Getting to Zero shows a hope to build up a new world without AIDS. In this paper we investigate and focus on those issues of the overall present scenarios of AIDS treatment for the preventive strategies of HIV infections. A mathematical model is analyzed with numerical simulations showing its importance in diseases control and preventions. Optimal control theory is applied to compare the results in the presence of state constraints.
- Preventive Antiretroviral Therapy in Non-Thalassemia Carrier Infants Exposed to Mother-to-Child Transmission of HIV Decreases Cord and After Delivery Red Blood Production Without Altering the Development of Hemoglobin. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Jul 13.
Antiretroviral (ARV) prophylaxis for prevention of mother to child transmission (MTCT) of HIV could affect hemoglobin (Hb) development of infants. A cross-sectional descriptive study was conducted in 24 HIV-infected and 21 HIV-uninfected pregnancies. ARV drugs were administered to HIV-infected pregnancies at 21 weeks of gestational age and at the labor. Their infants received zidovudine (ZDV) until 4 weeks of age. Blood sample of ARV-exposed and -unexposed infants were collected at delivery, 1, 2 and 4 months of age. Molecular analyses for α-thalassemia-1 Southeast Asian (SEA) type deletion, β-thalassemia mutations and Hb E were performed for excluding the thalassemia carrier infants. Hemoglobinopathy and Hb A, Hb F and Hb A2 were analyzed by using capillary electrophoresis (CE) while hematological parameters were measured using an automated blood counter. At delivery, 1 and 2 months of age, ARV-exposed infants had significantly lower levels of RBC counts than ARV-unexposed infants (3.56 vs 4.90, 2.66 vs 4.62 and 3.01 vs 4.05 x1012/L; P <0.001, <0.001 and 0.001, respectively). At delivery, there was a trend for low hemoglobin level in the group of ARV-exposed infants as compared to the group of ARV-unexposed infants (149 vs 154 g/L; P = 0.09) and the significantly different levels were observed among the two groups at 1 and 2 months of age (89 vs 136 and 87 vs 110 g/L; P < 0.001 and 0.001, respectively). The development of Hb A, Hb F and Hb A2 levels from delivery to 4 months of age among the two groups were not significantly different. Therefore, ARV treatments for prevention of MTCT of HIV decreased RBC counts and hemoglobin but did not alter the development of Hb A, Hb F and Hb A2 of non-thalassemia carrier infants.
- Mononuclear Phagocyte Accumulation in Visceral Tissue in HIV Encephalitis: Evidence for Increased Monocyte/Macrophage Trafficking and Altered Differentiation. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Jul 13.
The invasion of circulating monocytes/macrophages (Mφ)s from the peripheral blood into the central nervous system (CNS) appears to play an important role in the pathogenesis of HIV dementia (HIV-D), the most severe form of HIV-associated neurocognitive disorders (HAND), often confirmed histologically as HIV encephalitis (HIVE). In order to determine if trafficking of monocytes/Mφs is exclusive to the CNS or if it also occurs in organs outside of the brain, we have focused our investigation on visceral tissues of patients with HIVE. Liver, lymph node, spleen, and kidney autopsy tissues from the same HIVE cases investigated in earlier studies were examined by immunohistochemistry for the presence of CD14, CD16, CD68, Ki-67, and HIV-1 p24 expression. Here, we report a statistically significant increase in accumulation of Mφs in kidney, spleen, and lymph node tissues in specimens from patients with HIVE. In liver, we did not observe a significant increase in parenchymal macrophage accumulation, although perivascular macrophage accumulation was consistently observed with nodular lesions in 4 of 5 HIVE cases. We also observed an absence of CD14 expression on splenic Mφs in HIVE cases, which may implicate the spleen as a potential source of increased plasma soluble CD14 in HIV infection. HIV-1 p24 expression was observed in liver, lymph node and spleen but not kidney. Interestingly, renal pathology suggestive of chronic tubulointerstitial nephritis (possibly due to chronic pyelonephritis), including tubulointerstitial scarring, chronic interstitial inflammation and focal global glomerulosclerosis, without evidence of HIV-associated nephropathy (HIVAN), was seen in four of eight HIVE cases. Focal segmental and global glomerulosclerosis with tubular dilatation and prominent interstitial inflammation, consistent with HIVAN, was observed in two of the eight cases. Abundant cells expressing monocyte/Mφ cell surface markers, CD14 and CD68, were also CD16+ and found surrounding dilated tubules and adjacent to areas of glomerulosclerosis. The finding of co-morbid HIVE and renal pathology characterized by prominent interstitial inflammation may suggest a common mechanism involving the invasion of activated monocytes/Mφs from circulation. Monocyte/Mφ invasion of visceral tissues may play an important role in the immune dysfunction as well as comorbidity in AIDS and may, therefore, provide a high value target for the design of therapeutic strategies.
- DEFB1 5'UTR Polymorphisms Modulate the Risk of HIV-1 Infection in Mexican Women. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Jul 7.
Immunologic and genetic factors are involved in HIV-1/AIDS pathogenesis. Defensins are key molecules in innate immunity that participate in the control and/or development of infection and disease. Using PCR-RFLPs, we determined the association between HIV-1/AIDS and human β-defensin 1 (DEFB1) 5'UTR -52 G/A (rs1799946), -44 C/G (rs1800972), and -20 G/A (rs11362) polymorphisms in three groups of women from the state of Sinaloa, located in the Northwest region of Mexico: i) sex-workers; ii) healthy blood donors; and iii) HIV-1 patients. The -52GG genotype was more frequent in blood donors than in patients (p= 0.023; Odds Ratio, OR= 0.0.49; 95% CI = 0.25-0.95), whereas the -52GA genotype was significantly higher in patients (p= 0.013; OR= 2.03; 95% CI = 1.11"-"3.79, statistical power SP=98.8%), as well as the frequencies of -20A allele (p= 0.017; OR= 1.60; 95% CI = 1.06"-"2.40), -20AA genotype (p= 0.047; OR = 2.02; 95% CI = 0.93"-"4.33) and the ACA haplotype with respect to healthy blood donors (p= 0.000012; OR= 5.82; 95% CI = 2.33-16.43, SP= 99.89%) and sex-workers (p= 0.019; OR= 2.18; 95% CI = 1.07-4.46). Conversely, the ACG haplotype was higher in healthy blood donors than in patients (p= 0.009; OR= 0.55; 95% CI = 0.34-0.89). In addition, the -44CC genotype was associated with a low plasma viral load (p= 0.015), whereas AGA, AGG and GGA haplotypes were more prevalent in individuals with high CD4 counts (p= 0.004, 0.046, and 0.029, respectively). These findings associate DEFB1 5'UTR polymorphisms with HIV-1/AIDS in Mexican women for the first time.
- Identification of Essential cis Element in 5'UTR of Nef mRNA 1 for Nef Translation. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Jun 30.
Nef is one of the accessory proteins of the human immunodeficiency virus type 1 (HIV-1). Nef is translated from multiple-spliced mRNAs transcribed from the viral genome, whose mRNAs have a relatively long 5' untranslated region (5'UTR). Here, we identified a cis element in the 5'UTR of Nef mRNA essential for efficient Nef translation, which was named the Nef-translation essential region (NER). Mutants with a deleted NER in the 5'UTR of the HIV-1 NL4-3 strain showed an almost undetectable Nef expression owing to a low Nef translation efficiency. The NER of the NL4-3 strain was predicted to form putative stem loops. Although the 5'UTR showed significant but relatively low internal ribosome entry site (IRES) activity, the mechanism of 5'cap-dependent translation mainly contributed to the Nef translation from its Nef mRNA. Altogether, it was clarified that not only the 5' cap but also the NER in the 5'UTR is an essential cis element for efficient Nef translation, which is not a typical 5'-cap-dependent mechanism, and that there must be an as yet unknown mechanism using the NER for efficient Nef translation.
- Co-Evolution of Compensatory Mutation K43E with Mutation M41L in Long-Term HIV Antiretroviral Treatment. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Jun 17.
Background: Compensatory mutations have been observed to emerge with drug resistance (DR) mutations, but their effects on virological response to treatment have not been fully examined. In this study, we characterized the emergence and depletion dynamics of a compensatory mutation K43E that correlated with primary nucleoside reverse transcriptase inhibitor (NRTI) drug resistance mutations in Chinese HIV patients on antiretroviral treatment. Method: Single Genome Amplification (SGA) was used to obtain the HIV-1 pol gene quasispecies in three patients over 6 years of Antiretroviral Therapy (ART) treatment. SGA sequences were analyzed by Markov Chain Monte Carlo (MCMC) phylogenetic trees with molecular clock to identify and track compensatory mutation K43E correlated with primary DR mutation M41L. We evaluated the relationship between potential compensatory mutation and DR mutations through Ka/Ks ratio, Jaccard similarity coefficient, and compared these with concurrent viral load data. Conclusion: We determined that a known compensatory mutation, K43E, frequently co-occurs with the drug resistance mutation M41L and may offer a significant advantage in the long-term survival of such drug resistant strains.
- Determinants of HIV Counseling and Testing Uptake among Individuals in Long-term Sexual Relationships in Uganda. [JOURNAL ARTICLE]
- Curr HIV Res 2014 May 30.
Introduction: Studies show that HIV counseling and testing (HCT) can improve linkage to HIV prevention, care and treatment services. However, uptake of HCT among couples remains low in most settings. We investigated the determinants of HCT uptake among individuals in long-term relationships in two districts in Uganda. Methods: This case-control study was conducted among 787 (400 in Kampala and 387 in Soroti) individuals in long-term sexual relationships, aged 18-54 years, using interviewer-administered questionnaires. Cases were individuals who had ever tested for HIV (selected from health facility records and traced in the community for interview) while controls were individuals who had never tested for HIV, identified from the same community as the cases. Data were collected on socio-demographic and behavioral characteristics; entered into FoxPro and analyzed using STATA version 12.1. We performed multivariable logistic regression to estimate the odds ratio (OR) and 95% Confidence Intervals (95%CI) associated with prior HCT and couples' HCT uptake, controlling for suspected confounders. Results: Of the 787 participants, 522 had ever tested for HIV (cases) while 265 had never tested for HIV (controls). Compared to those that had never tested for HIV, those that had ever tested for HIV were significantly more likely to be females (Adj. OR=3.23, 95%CI: 2.27, 4.60), to be 25-29 years old (Adj. OR=2.15, 95%CI: 1.32, 3.50), to report exposure to a couples' HCT promotional campaign (Adj. OR=2.01, 95%CI: 1.30, 3.10) and to believe that HIV discordance is possible among married couples (Adj. OR=1.77, 95%CI: 1.20, 2.63). Compared to individuals that had ever received individual HCT, those that had ever received couples' HCT were significantly more likely to report prior discussion of HIV testing with partner (Adj. OR=4.35, 95%CI: 2.61, 7.28) and to be residents of Soroti district (Adj. OR=6.01, 95%CI: 3.74, 9.65). Conclusion: Prior HCT was significantly associated with female gender and exposure to a couples' HCT promotional campaign while prior couples' HCT was significantly associated with prior discussion of HIV testing with partner. To increase HIV testing among couples, these findings suggest a need for HCT promotional campaigns that promote communication about HCT between partners.
- Cognitive Consequences of a Sustained Monocyte Type 1 IFN Response in HIV-1Infection. [JOURNAL ARTICLE]
- Curr HIV Res 2014 May 26.
With successful antiretroviral therapy, HIV-1-infected subjects can achieve undetectable peripheral viral loads and immune homeostasis. However, in a subset of individuals on therapy, peripheral monocytes have a gene expression profile characteristic of a type 1 interferon α (IFN) response. This type 1 IFN response correlates with a number of pathogenic conditions including neural cell injury and in combination with HCV infection, cognitive impairment. Lessons from the non-human primate models of pathogenic and nonpathogenic SIV suggest that returning the initial IFN spike in acute SIV infection to normal allows the immune system to control infection and return to homeostasis. AnIFN "alarm" signature,defined as monocyte activation with over expression of the type1 IFN genes IF127 and SN,would be useful for identifying a subset of subjects with HIV-1 infection that could progress to a number of pathologies associated with immune activation including cognitive dysfunction. This strategy is being actively pursued for autoimmune diseases that are characterized by an IFN signature. Therapies to block the IFN signature are under investigation as a means to reset the immune system and in a subset of HIV-1-infected subjects may be an adjuvant to standard antiviral therapy to return cognitive function.
- Monocytes Mediate HIV Neuropathogenesis: Mechanisms that Contribute to HIV Associated Neurocognitive. [JOURNAL ARTICLE]
- Curr HIV Res 2014 May 26.
HIV infected people are living longer due to the success of combined antiretroviral therapy (cART).However, greater than 40-70% of HIV infected individuals develop HIV associated neurocognitive disorders (HAND) that continues to be a major public health issue. While cART reduces peripheral virus, it does not limit the low level, chronic neuroinflammation that is ongoing during the neuropathogenesis of HIV. Monocyte transmigration across the blood brain barrier (BBB), specifically that of the mature CD14+CD16+ population that is highly susceptible to HIV infection, is critical to the establishment of HAND as these cells bring virus into the brain and mediate the neuroinflammation that persists, even if at low levels, despite antiretroviral therapy. CD14+CD16+ monocytes preferentially migrate into the CNS early during peripheral HIV infection in response to chemotactic signals, including those from CCL2 and CXCL12. Once within the brain, monocytes differentiate into macrophages and elaborate inflammatory mediators. Monocytes/macrophages constitute a viral reservoir within the CNS and these latently infected cells may perpetuate the neuropathogenesis of HIV. This review will discuss mechanisms that mediate transmigration of CD14+CD16+ monocytes across the BBB in the context of HIV infection, the contribution of these cells to the neuropathogenesis of HIV, and potential monocyte/macrophage biomarkers to identify HAND and monitor its progression.