Current HIV Research (v.11, #1)
Preface by Charles Wood (1-1).
The Origin of Lentivirus Research: Maedi-Visna Virus by Halldor Thormar (2-9).
Maedi and visna are contagious sheep diseases which were introduced into Iceland in 1933 by imported sheep of Karakul breed. Maedi, a slowly progressing pneumonia, and the central nervous system disease visna were shown to be transmissible in sheep and most likely caused by a virus. In 1957, visna virus was isolated in tissue culture from sheep brain and maedi virus was isolated the following year from sheep lungs. Both viruses showed similar cytopathic effect in tissue culture. Electron microscope studies of ultrathin sections from visna virus infected cells demonstrated spherical particles, 70-100 nm in diameter, which were formed by budding from the cell membrane. Later studies showed identical particles in maedi virus infected cultures. These, and several other comparative studies, strongly indicated that maedi and visna were caused by strains of the same virus, later named maedi-visna virus (MVV). Comparative studies in tissue culture suggested that MVV was related to RNA tumor viruses of animals, the oncornaviruses. This was later supported by the finding that MVV is an RNA virus. A few months after reverse transcriptase was demonstrated in oncornaviruses, the enzyme was also found in MVV virions. Thus, MVV was classified as a retrovirus together with the oncornaviruses. However, MVV is not oncogenic in vivo or in vitro and was in 1975 placed in a subgroup of retroviruses named lentiviruses, which cause cytopathic effect in vitro and slowly progressing inflammatory disease in animals, but are nononcogenic. In the early 1980s, the causative agent of AIDS was found to be a non-oncogenic retrovirus and was classified as a lentivirus. Thus, HIV became the first human lentivirus.
The Role of Co-Infections in Mother-to-Child Transmission of HIV by Caroline C. King, Sascha R. Ellington, Athena P. Kourtis (10-23).
In HIV-infected women, co-infections that target the placenta, fetal membranes, genital tract, and breast tissue, as well as systemic maternal and infant infections, have been shown to increase the risk for mother-to-child transmission of HIV (MTCT). Active co-infection stimulates the release of cytokines and inflammatory agents that enhance HIV replication locally or systemically and increase tissue permeability, which weakens natural defenses to MTCT. Many maternal or infant co-infections can affect MTCT of HIV, and particular ones, such as genital tract infection with herpes simplex virus, or systemic infections such as hepatitis B, can have substantial epidemiologic impact on MTCT. Screening and treatment for co-infections that can make infants susceptible to MTCT in utero, peripartum, or postpartum can help reduce the incidence of HIV infection among infants and improve the health of mothers and infants worldwide.
Histone Deacetylase Inhibitor MC1293 Induces Latent HIV-1 Reactivation by Histone Modification In Vitro Latency Cell Lines by Xiying Qu, Hao Ying, Xiaohui Wang, Chuijin Kong, Xin Zhou, Pengfei Wang, Huanzhang Zhu (24-29).
HIV-1 latency remains a major problem for the eradication of viruses in infected individuals. We evaluated the effect of MC1293 on the epigenetic change at HIV-1 LTR and the induction of the latent viruses in the latency Jurkat T cell line. We found MC1293 can activate HIV-1 gene expression, increase the acetylation level of H3 and H4 at the nuc-1 site of HIV-1 LTR. In addition, MC1293 can synergize with prostratin to activate the HIV-1 promoter, and has relatively lower toxicity compared to Trichostatin A (TSA). The results suggest that the acetylation of histone plays an important role in regulating HIV-1 LTR gene expression, and MC1293 is potential drug candidate for antilatency therapies.
HIV Progression to AIDS: Bioinformatics Approach to Determining the Mechanism of Action by Norbert Nwankwo, Huseyin Seker (30-42).
The mechanism by which HIV infection transforms into AIDS disease is unclear. Several factors such as the decline in immune response, increase in replication rate, Syncytium inducing capacity and ability of the viruses to infect tumour cell lines are found to be associated with HIV progression to AIDS. What has not been investigated is the role of an increase in affinity for the CD4+ T cells by the HIV-1 T cell lymphocyte-loving (T-tropic) viruses. They are known to be mutants of the Macrophage-loving (M-tropic) viruses and dominate the late stage of the HIV infection in the disease progression. To elucidate the mechanism by which HIV is transformed into AIDS, this role is examined by using the Resonant Recognition Model (RRM). This is achieved by comparing the degree of affinity between the host CD4 and the gp120 from the HIV-1 M-tropic and HIV-1 T-tropic viruses as well as the isolates of HIV-2 and Simian immunodeficiency virus (SIV). The results reveal that only HIV-1 T-tropic viruses bind effectively to the CD4 suggesting that T-tropic viruses, which were identified to have mutated from the M-tropic viruses, acquire enhanced and long-lasting attachment to the CD4. This sustained affinity brings about continued attack on the diminishing CD4 until the immune system of the host collapses, which manifests clinically as AIDS. The findings therefore suggest an approach that should target the Variable region 3 (V3) of the HIV-1 gp120 at the early stage of the infection as a part of the HIV/AIDS management procedure. This procedure is essential as early initiation of HIV/AIDS therapy is generally assumed to prevent the spread of the virus and deterioration of the host immunity. The study is expected to help better understand the HIV pathogenesis and re-strategise pharmaceutical approaches to designing new HIV/AIDS therapeutic interventions.
Low-Abundance Resistant Mutations in HIV-1 Subtype C Antiretroviral Therapy-Naive Individuals as Revealed by Pyrosequencing by Sandra Gonzalez, Damien C. Tully, Clement Gondwe, Charles Wood (43-49).
Given the recent scale-up of antiretroviral therapy (ART) in sub-Saharan Africa, we sought to determine how often and at what levels do drug-resistant mutant variants exist in ART-naive HIV subtype C infected individuals. Samples from 10 ART-naive Zambian individuals were subjected to ultra-deep pyrosequencing (UDPS) to characterize the frequency of low-abundance drug resistance mutations in the pol gene. Low-abundance clinically relevant variants were detected for nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in eight of the ten subjects. Intermediate to high-level resistance was predicted for the majority of NRTIs. Mutations conferring resistance to most first-line and some second-line therapy drugs were also observed. UDPS detected a number of additional major resistant mutations suggesting that these individuals may have an increased risk of virological failure after initiating ART. Moreover, the effectiveness of first-line and even some secondline ART may be compromised in this setting.
IL28B Polymorphism, Blood Interferon-Alpha Concentration, and Disease Stage of HCV Mono-Infected and HCV-HIV Co-Infected Patients by Michela E. Burlone, Andrea Cerutti, Rosalba Minisini, Carlo Smirne, Elisa Boccato, Elisa Ceriani, Giovanni Rizzo, Olivia Bargiacchi, Simone Bocchetta, Giuseppa Occhino, Mario Pirisi (50-55).
Interferon (IFN) preactivation, interleukin-28B (IL28B) alleles, and liver fibrosis act as predictors of response to antiviral therapy against hepatitis C. We aimed to verify if blood IFN concentration, a putative biomarker of interferon preactivation, might depend on carriage of a given IL28B genotype and/or advanced hepatic fibrosis. The study population included 187 hepatitis C patients (75 of whom were HIV coinfected), who were genotyped for the rs12979860 polymorphism and staged non-invasively by transient elastography. Blood IFN, measured by an enzyme immunoassay, was detectable in 68/187 patients (36%). Seventy-three patients (39%) were C/C homozygotes, 25 (13%) were T/T homozygotes, and 89 (48%) were heterozygotes. The fibrosis stage was F0-F1 in 70 patients (37%), F2-F3 in 54 patients (29%), and F4 in 63 patients (34%). IFN levels were higher among patients with HIV coinfection (p=0.044) and patients with better renal function (p=0.041), without association with the IL28B genotype or the hepatitis C stage. From the multivariate analysis, the only independent predictor of higher level of IFN was the age of patients (p=0.019), whereas independent predictors of a fibrosis stage ≥F2 were age (p=0.007), belonging to the HIV/HCV group (p=0.048) and current alcohol consumption (p=0.008). In conclusion, a sizable proportion of HCV carriers have detectable IFN levels that do not indicate a greater severity of disease or display any relationships to specific rs12979860 variants.
An Effective Vaccination Approach Augments Anti-HIV Systemic and Vaginal Immunity in Mice with Decreased HIV-1 Susceptible α4β7high CD4+ T Cells by Wei Zhu, Guoping Shi, Haijun Tang, Dorothy E. Lewis, Xiao-Tong Song (56-66).
HIV-1 preferentially infects activated CD4+ T cells expressing α4β7 integrin and conventional vaccination approaches non-selectively induce immune responses including α4β7high CD4+ T cells, suggesting that current candidate AIDS vaccines may produce more target cells for HIV-1 and paradoxically enhance HIV-1 infection. Thus it remains a challenge to selectively induce robust anti-HIV immunity without the unwanted HIV-1 susceptible α4β77high CD4+ T cells. Here we describe a vaccination strategy that targets ALDH1a2, a retinoic acid producing enzyme in dendritic cells (DCs). Silencing ALDH1a2 in DCs enhanced the maturation and production of proinflammatory cytokines of DCs and promoted Th1/Th2 differentiation while suppressing Treg. ALDH1a2-silenced DCs effectively downregulated the expression of guthoming receptors α4β77 and CCR9 on activated T and B lymphocytes. Consequently, intranasal immunization of a lentiviral vaccine encoding ALDH1a2 shRNA and HIV-1 gp140 redirected gp140-specific mucosal T cell and antibody responses from the gut to the vaginal tract, while dramatically enhancing systemic gp140-specific immune responses. We further demonstrated that silencing ALDH1a2 in human DCs resulted in downregulation of β7 expression on activated autologous CD4+ T cells. Hence this study provides a unique and effective strategy to induce α4β7low anti-HIV immune responses.
The Beneficial Role of Vitamin D in Human Immunodeficiency Virus Infection by Khanh vinh quoc Luong, Lan Thi Hoang Nguyen (67-78).
Patients with human immuno-deficiency virus (HIV)-infection have a high prevalence of abnormal bone metabolism and vitamin D deficiency. Vitamin D treatment has some benefit in patients with HIV infection. In this paper, we review the evidence for an association between vitamin D and HIV infection. Literature search was done from Medline. Genetic studies have provided the opportunity to determine which proteins link vitamin D to HIV pathology [i.e., the major histocompatibility complex class II molecules, vitamin D receptor, cytochrome P450, renin-angiotensin system, apolipoprotein E, liver X receptor, toll-like receptor, poly(ADP-ribosyl) polymerase-1, natural resistanceassociated macrophage protein 1, and the Sp1 promoter gene]. Vitamin D also exerts its effect on HIV through nongenomic factors, i.e., ultraviolet radiation exposure, matrix metalloproteinase, heme oxygenase-1, the prostaglandins, cyclooxygenase-2, and oxidative stress. In conclusion, vitamin D may have a beneficial role in HIV. Calcitriol, 1α,25-dihydroxyvitamin D3 should be tested in HIV-infected population because of its active form of the vitamin D3 metabolite and modulates inflammatory cytokine expression. Further investigation with calcitriol in HIV is needed.