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Current HIV Research (v.6, #5)

Cellular Reservoirs of HIV-1 and their Role in Viral Persistence by Aikaterini Alexaki, Yujie Liu, Brian Wigdahl (pp. 388-400).
A major obstacle in human immunodeficiency virus type 1 (HIV-1) eradication is the ability of the virus to remain latent in a subpopulation of the cells it infects. Latently infected cells can escape the viral immune response and persist for long periods of time, despite the presence of successful highly active antiretroviral therapy (HAART). Given the appropriate stimulus, latently infected cells can reactivate and start producing infectious virions. The susceptibility of these cell populations to HIV-1, their life span, their proliferative capacity, and their ability to periodically produce infectious virus subsequent to alterations in cellular physiology and/or immunologic controls are critical issues which determine the contribution of these cells to viral persistence. Memory CD4+ T cells due to the long life span, which may be several years, and their ability to reactivate upon encounter with their cognate antigen or other stimulation, are considered a critical reservoir for maintenance of latent HIV-1 proviral DNA. Cells of the monocyte-macrophage lineage, which originate in the bone marrow (BM), are of particular importance in HIV-1 persistence due to their ability to cross the blood-brain barrier (BBB) and spread HIV-1 infection in the immunoprivileged central nervous system (CNS). Hematopoietic progenitor cells (HPCs) are also a potential HIV-1 reservoir, as several studies have shown that CD34+ HPCs carrying proviral DNA can be found in vivo in a subpopulation of HIV-1-infected patients. The ability of HPCs to proliferate and potentially generate clonal populations of infected cells of the monocyte-macrophage lineage may be crucial in HIV-1 dissemination. The contribution of these and other cell populations in HIV-1 persistence, as well as the possible strategies to eliminate latently infected cells are critically examined in this review.

Combining Drug and Immune Therapy: A Potential Solution to Drug Resistance and Challenges of HIV Vaccines? by Aaron Endsley, Noha Salama, Rodney Ho (pp. 401-410).
According to the World Health Organization's 2007 estimates, close to 33 million people worldwide are living with HIV/AIDS. Over the past two decades, significant progress has been made in understanding HIV pathogenesis and disease progression, which has allowed the identification of a multitude of drug and vaccine targets. Although currently available drug therapies have greatly increased the time from HIV infection to development of AIDS, drug resistance is an inevitable consequence that limits the duration of successful treatment. Consequently, a preventative vaccine remains the top priority; however, no vaccine trial performed to date has shown efficacy in human trials. Therefore, we must use all of our current resources in new creative therapies and strive to develop new methods to reduce persistent viral levels until an effective preventative vaccine is developed. One possible strategy is to use therapeutic vaccination or immune modulators to augment the immune response while antiretroviral chemotherapy limits viral replication. This combination approach is being utilized with success in the treatment of Hepatitis B infections and several trials have been completed and others are ongoing to determine the potential of combination immunological and chemical therapies for HIV infection. We will review the progress to date of anti-HIV drugs, preventative vaccines, and therapeutic vaccines and discuss the future strategies of combination drug and vaccine therapeutic strategies in the fight against HIV.

Platelets and HIV-1 Infection: Old and New Aspects by Donato Torre, Agostino Pugliese (pp. 411-418).
In this review we summarize the data on interaction of platelets with HIV-1 infection. Thrombocytopenia is a common finding among HIV-1 infected patients; several combined factors contribute to low peripheral platelet counts, which are present during all the stages of the disease. In addition, a relationship between platelet count, plasma viral load and disease progression has been reported, and this shows the potential influence platelets may have on the natural history of HIV-1 disease. Several lines of evidence have shown that platelets are an integral part of inflammation, and can be also potent effector cells of innate immune response as well as of adaptive immunity. Thus, we rewieved the role of inflammatory cytokines, and chemokines as activators of platelets during HIV-1 infection. Moreover, platelets show a direct interaction with HIV- 1 itself, through different pathogenic mechanisms as binding, engulfment, internalisation of HIV-1, playing a role in host defence during HIV-1 infection, by limiting viral spread and probably by inactivating viral particles. Platelets may also play an intriguing role on endothelial dysfunction present in HIV-1 infection, and this topic begins to receive systematic study, inasmuch as interaction between platelets and endothelial cells is important in the pathogenesis of atherosclerosis in HIV-1 infected patients, especially in those patients treated with antiretroviral drugs. Finally, this review attempts to better define the state of this emerging issue, to focus areas of potential clinical relevance, and to suggest several directions for future research.

The Indian Pediatric HIV Epidemic: A Systematic Review by Harjot Singh, Amita Gupta, George Siberry, Nikhil Gupte, Jayagowri Sastry, Arti Kinikar, Ira Shah, Raman Gangakhedkar, Robert Bollinger, Vinay Kulkarni (pp. 419-432).
Despite an estimated 70,000 Indian children living with HIV infection, little is known about India's pediatric HIV epidemic. Generalizations about epidemiology, natural history, and treatment outcomes from other resource-limited settings (RLS) may be inaccurate for several biologic and social reasons. A review of the Indian literature is needed to optimize country-specific HIV management and examine these generalizations. MEDLINE and EMBASE were searched for articles published in English by November 2007 on HIV-infected, Indian children (0-18 years) that detailed epidemiology, natural history, or treatment. Articles with original, extractable data were selected and summarized using descriptive statistics. Of 370 citations, 58 studies were included in this review (median study size 24 children). Significant heterogeneity was noted among the studies. HIV infection was reported nearly twice as often in males (male/female ratio 1.9) and diagnosed earlier (4.7 years) than in other RLS. Over 2and#x25; of hospitalized children were reported to be HIV-infected. The reported mortality among HIV-infected newborns of 22and#x25; at 18 months was lower than other RLS. Improved anthropometrics were the only consistently reported and comparable benefit of short-term HAART to other RLS. Review of the Indian literature yielded potentially unique epidemiology and natural history compared to other RLS. However, important questions about the accuracy and representativeness of the Indian data limit its generalizability and comparability. Targeted interventions to curb India's pediatric HIV epidemic require urgent clarification of these findings. If such differences truly exist, management guidelines should be tailored accordingly.

NK Cell Function in HIV-1 Infection by Andrea De Maria, Lorenzo Moretta (pp. 433-440).
The parallel development of precise knowledge on NK cell receptors and on their function has considerably supported our understanding of the extension of their involvement during HIV-1 infection. The relevant reduction of NK cell function is dependent on well-described perturbations of their expression of specific receptors, leading not only to inhibition of their patrolling activity against invading pathogens, but also to alterations of their crosstalk with other cells of the immune system. With NK cell failure, boosted viral replication reduces immune surveillance towards opportunistic neoplasm and impaired control of adaptive responses prevails. NK cell function in human and animal models showing efficient control of disease progression may offer new insights in mechanisms underlying the protection from infectious disease.

HHV-6 is Frequently Detected in Dried Cord Blood Spots from Babies Born to HIV-Positive Mothers by Pierlanfranco D'Agaro, Paola Burgnich, Manola Comar, Gianna Molin, Maria Bernardon, Marina Busetti, Salvatore Alberico, Albino Poli, Cesare Campello, the SIGO Italian Group (pp. 441-446).
Intrauterine transmission of HHV-6 is well established in immunocompetent women while few data are available on infections in babies born to HIV-positive mothers. To assess the rate of HHV-6 vertical transmission in comparison to CMV, we analyzed cord blood spots dried on cards (Dried Blood Spots, DBS) collected during a multi-center study on HIV congenital infections in Italy. DBS were tested by PCR for HHV-6 and CMV footprints. HHV-6 amplimers were sequenced and characterized. As control group, cards taken from babies born to HIV-negative mothers were analyzed. DBS of 187 babies born to HIV-positive and 372 to HIV-negative mothers were analyzed. The prevalence of HHV-6 was 3.2and#x25; in babies born to HIV-positive mothers. CMV was found in the HIV-positive group with a prevalence rate of 1.6and#x25;. In newborns of control pregnant women, HHV-6 prevalence rate was 1.1and#x25; (p=0.09), while CMV was not detected (p=0.04). Sequence analysis could distinguish between HHV-6 A and B variant in both groups and one A/B coinfection was found in a baby born to a HIV-positive mother. HIV-infected mothers transmit HHV-6 and CMV viruses to their babies more frequently than uninfected women.

Effect of HAART on Salivary Composition and Oxidative Profile in HIVInfected Patients by Eduardo Shahar, Shimon Pollack, Eynat Kedem, Gammal Hassoun, Rafael Nagler (pp. 447-451).
Although it has been widely suggested that oxidative stress contributes to the pathogenesis of HIV infection, salivary composition and its oxidative related aspects have never been studied in HIV patients, both HAART-treated and untreated. Human saliva and serum were collected and analyzed for various biochemical, redox related and immunological parameters from 43 consenting HIV-infected patients (20 untreated and 23 treated with HAART) and 20 healthy controls, age and gender matched. Saliva composition of HIV infected patients was completely altered but returned to normal following HAART. HIV patients had significantly-increased levels of oxidative stress damaging markers, compared to healthy controls. Carbonyl levels increased by 110and#x25; (p=0.005), and superoxide dismutase enzyme (SOD) and antioxidant capacity (ImAnOx) levels by 45and#x25; and 16and#x25; (0.035) respectively, but returned to normal levels in treated patients (p=0.005, p=0.03 and 0.02 respectively). Also, the significantly-altered salivary composition (pH and lactate dehydrogenase (LDH) enzyme) and concentration (calcium (Ca), magnesium (Mg), albumin, salivary total protein, secretory IgA) of HIV-infected patients reverted to normal following HAART treatment. Salivary analysis may be used for assessing patient status: treated vs untreated, based on the increase or decrease in the concentration of a given salivary parameter in the HIV-untreated group vs controls, and a return to normal following the HAART treatment. Salivary collection is simple, non-invasive and not associated with risk of infection spread. Antioxidants in HIV patients may be recommended, as well as local oral means aimed at resuming salivary functions compromised in HIV patients.

Anti-HIV-1 and Anti-HBV Immune Responses in Mice After Parenteral and Nasal Co-Administration of a Multiantigenic Formulation by Enrique Iglesias, Daymir Garcia, Yamilka Carrazana, Julio Aguilar, Aniel Sanchez, Lariza Gorobaya, Aracelys Blanco (pp. 452-460).
The cell-mediated immune response to HIV-1 is an essential element of the mechanisms for viral replication control. Currently, most of the vaccine candidates in clinical trials were developed to stimulate HIV-1-specific CD8+ cytotoxic (CTL) and CD4+ T helper (Th) lymphocytes. We have been working on a novel approach to develop a vaccine formulation for HIV-1 using a recombinant multiepitopic protein (named CR3), which comprises CTL and Th epitoperich regions of HIV-1 from several subtype B isolates, co-inoculated with the hepatitis B virus surface (HBsAg) and core (HBcAg) antigens of the hepatitis B virus (HBV) as adjuvant. According to our studies in mice, the nasal-subcutaneous co-administration of this multiantigenic formulation induces a strong Th1-biased specific response against CR3, CD8+ T cells in mice spleen and IFN-and#947;-secreting cells in mesenteric lymph nodes. Cross-reactive p24-specific IFN-and#947;-secreting cells in spleen were also detected. Moreover, Nef-specific antibodies were elicited in mice sera which might avoid the toxic effects of this antigen. However, a marginal anti-CR3 antibody response was elicited in vaginal mucosa. Additionally, we observed anti-HBsAg and anti-HBcAg cellular and humoral responses. In this regard, our multiantigenic formulation might provide immunity against HBV as an additional benefic considering the high HIV-1-HBV co-infection rate reported worldwide.

Development and Evaluation of Single Sperm Washing for Risk Reduction in Artificial Reproductive Technology (ART) for Extreme Oligospermic HIV Positive Patients by Alionka Bostan, Anne-Sophie Vannin, Serena Emiliani, Laurent Debaisieux, Corinne Liesnard, Yvon Englert (pp. 461-465).
The serodiscordant couples, where the male is HIV-positive, are treated in fertility clinics, using the sperm washing technique by gradient centrifugation. This protocol cannot be carried out in oligo-azoospermic patients, where spermatozoa retrieval from the epididymis and testis must be performed. We developed a single sperm washing technique, where the spermatozoa, after the retrieval, are washed with the aid of a micromanipulator, to obtain virus decontamination and then used for the intracytoplasmic sperm injection (ICSI). The experiment was performed by using sperm samples containing three different viral loads. After one hour of incubation, spermatozoa were taken one by one from the HIV loaded drop and washed in four different microdrops. Before each passage into the next washing drop, the pipette was emptied in a first waste drop and then loaded with new washing medium from a second separate loading drop. After transferring of 10 spermatozoa in these four successive drops, the washing medium and the virus-loaded drops were tested for the HIV RNA presence by the nested RT-PCR technique. The presence of the virus was detected in the waste drop of all three viral loads. The four washing microdrops were each time negative for the presence of HIV-1 RNA, tested by the nested RT-PCR technique. The results show that by rinsing the spermatozoa four times, we are able to diminish the viral load to an undetectable level. Our data demonstrate that single sperm washing can be performed in the cases of extreme male sterility in HIV-positive men. From now on the couples, where the male is oligoazoospermic and HIV positive, could be included in our ICSI program, respecting the usual viral safety level of the ART techniques for the embryo.

Better CD4+ T Cell Recovery in Brazilian HIV-Infected Individuals Under HAART Due to Cumulative Carriage of SDF-1-3'A, CCR2-V64I, CCR5- D32 and CCR5-Promoter 59029A/G Polymorphisms by Paula Rigato, Marisa Hong, Jorge Casseb, Mirthes Ueda, Isac de Castro, Gil Benard, Alberto Duarte (pp. 466-473).
Polymorphisms of chemokines and chemokine-receptors genes have been shown to influence the rate of progression to AIDS; however, their influence on response to HAART remains unclear. We investigated the frequency of the SDF-1-3'A, CCR2-64I, CCR5-D32 and CCR5-Promoter-59029-A/G polymorphisms in Brazilian HIV-1-infected and uninfected individuals and their influence on CD4+ T-cell evolution HIV-1 infected individuals before and during HAART. Polymorphism detection was done in a transversal study of 200 HIV-1-infected and 82 uninfected individuals. The rate of CD4+ T cell increase or decrease was studied in a cohort of 155 HIV-1 infected individuals on pre and post-HAART. Polymorphisms were determined by PCR associated with RFLP. The rate of CD4+ T-cell decline or increase was also determined. HIV-1 infected and uninfected subjects showed, respectively, frequencies of 0.193 and 0.220 for SDF-1-3'A, of 0.140 and 0.110 for CCR2-V64I, of 0.038 and 0.055 for CCR5-D32, and of 0.442 and 0.390 for CCR5-P-59029-A/G. HIV-1-infected subjects carrying one, two or three of these four polymorphisms showed better CD4+ T-cell recovery than HIV-1-infected subjects carrying the four wild-type alleles (+2.7, +1.6, +3.5, and -0.9 lymphocytes/and#956;l/month, respectively). Regression logistic analysis showed that the CCR5-D32/CCR2-V64I association was predictor of positive CD4+ T cell slope after HAART. The distribution of polymorphisms did not differ between HIV-1-infected and uninfected individuals, but differed from more homogenous ethnic groups probably reflecting the miscegenation of the Brazilian population. We add further evidence of the role of these polymorphisms by showing that the CD4 gain was influenced by carriage of one or more of the polymorphisms studied here. These results highlight the possibility that these genetic traits can be useful to identify patients at risk for faster progression to AIDS or therapeutic failure.

Evaluating the Role of Etravirine in the Second-Line Antiretroviral Therapy After Failing an Initial Non-Nucleoside Reverse Transcriptase Inhibitor- Based Regimen in a Resource-Limited Setting§ by Somnuek Sungkanuparph, Weerawat Manosuthi, Sasisopin Kiertiburanakul, Bucha Piyavong, Wasun Chantratita (pp. 474-476).
Etravirine demonstrates activity against NNRTI-resistant HIV-1 but its efficacy depends on the number of etravirine resistance-associated mutations (RAMs). This study aimed to evaluate the role of etravirine in the second regimen in a resource-limited setting. Genotype resistance assay was conducted in a cohort of HIV-infected patients who experienced virological failure from an initial NNRTI-based regimen. We focused on etravirine-RAMs previously described: V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S. Frequency and predicting factors for 2 etravirine- RAMs were evaluated. There were 158 patients with a median duration of ART prior to failure of 22 months. The median CD4 cell count and HIV-1 RNA at the time of virological failure were 173 cells/mm3 and 4.1 log copies/mL, respectively. Of all, 75.3and#x25; of patients were predicted to have 2 etravirine-RAMs. From logistic regression, there was no clinical factor to predict etravirine susceptibility. Patients with 2 etravirine-RAMs had lower rates of K65R (3.4and#x25; vs 17.9and#x25;, p=0.005), Q151M (5.9and#x25; vs 20.5and#x25;, p=0.012), and multi-NRTI resistance mutations (16.8and#x25; vs 48.7and#x25;, p andlt; 0.001) when compared to patients with > 2 etravirine-RAMs. Etravirine may have activity for using in the second regimen in most patients in resource-limited setting who fail an initial NNRTI-based regimen. Genotype testing is needed to identify this group. Some of these patients, indicated by genotype results, may be able to use etravirine plus 2 active NRTIs for second ART regimen. This strategy may be an option for patients who cannot afford or tolerate protease inhibitor. Prospective study to evaluate this strategy should be conducted in resource-limited setting.

Correlation Between HIV-1 RNA Load in Blood and Seminal Plasma Depending on Antiretroviral Treatment Status, Regimen and Penetration of Semen by Antiretroviral Drugs§ by Derek Chan, John Ray, Leon McNally, Marijka Batterham, Don Smith (pp. 477-484).
To assess the correlation between HIV-1 RNA load in blood and semen by antiretroviral therapy status and the relative penetration of antiretroviral drugs in seminal plasma. We performed a cross-sectional cohort study of 119 HIV-1 subjects divided into three groups according to treatment status. Blood and semen were collected concurrently. Seminal viral load determined by NucliSensand#174; HIV-1 QT PCR (BioMerieux). Viral suppression over time was assessed in a second semen sample collected from 10 treated subjects. Antietroviral plasma concentrations were measured by high performance liquid chromatography and recovery experiments were performed on semen samples to validate quantitation in this matrix. All subjects taking non nucleoside reverse transcriptase inhibitors (n = 36, mean treatment 33 months and#xB1; 14) or protease inhibitors (n = 45, mean treatment 31 months and#xB1; 25) had blood viral load andlt; 50 copies/mL and seminal viral load andlt; 250 copies/mL. In untreated subjects (n = 38), blood and semen viral loads were positively correlated (Spearman's p = 0.489, p = 0.002). Blood and semen nevirapine concentrations were positively correlated (r2 = 0.795, p = 0.005) and therapeutic concentrations achieved in both compartments. Lopinavir and atazanavir also penetrated semen but efavirenz did not. We find that there is compartmentalisation of HIV-1 within the male genital tract and propose that new infections may originate from untreated men and that suppressive antiretroviral regimens may reduce the risk of sexual transmission.
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