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PubMed2006

Transmitted multidrug resistant HIV-1: new and investigational therapeutic approaches.

The increasing prevalence of transmitted drug-resistant HIV-1 has highlighted the challenging issue of the optimal management of antiretroviral-naïve, newly infected patients with multidrug-resistant HIV-1. This review discusses current trends in the evolution and transmission of HIV-1 with reduced susceptibility to multiple antiretroviral agents. In most cases, clinical strategies for the management of such patients with stable virological and immunological parameters involve deferment of therapy until clinically indicated. When a decision is made to initiate therapy, the process of selecting a regimen should consider baseline viral genotype and phenotype results, as well as the inclusion of novel agents with diverse mechanisms of action, in order to achieve a more complete suppression of viral replication. A summary of established and investigational antiretroviral agents is presented in this review, together with novel therapeutic approaches to decrease the burden of viral replication and maintain immunological status in cases of transmitted multidrug-resistant HIV-1 infection.

Anti-HIV Agents↗
PubMed2004

[Epidemiology of human immunodeficiency virus (HIV) infection in the province of Salamanca (1985-2002)].

INTRODUCTION: Since effective treatment against HIV has become available, HIV infection surveillance is focussed not only on AIDS cases, but also on new cases of HIV infection. One of the methods used for this task is compilation of case records. We report the results of 18 years of recording information on new diagnoses of HIV (1985-2002) in the area of Salamanca (Spain). METHODS: Our report system is based on active monitoring of results from the microbiology laboratory of the Salamanca Health Area. All patients testing positive in HIV analytical studies and who had not been previously diagnosed as HIV-infected are included in the report system. RESULTS: A total of 188 579 analytical results were studied. We found 16,772 (9.23%) HIV-positive results, 1984 of which were new HIV infection diagnoses. The incidence for the entire period was 556 cases/100,000 inhabitants. The highest incidence was found in 1992 (62.2 cases/100,000), with a progressive decrease thereafter to 2002 (5.18/100,000). Among the total, 75.3% of patients were men between 20 and 39 years old and more than half (62.2%) were intravenous drug users. Over the period studied, there has been an increase in the age of patients at the time of diagnosis, a trend to increases in the number of cases acquired through heterosexual transmission and a reduction in the number of drug users. During the study period, 312 AIDS cases were declared. CONCLUSIONS: Epidemiological information systems for HIV surveillance are essential to know the features, magnitude and evolution of the epidemic. Creation of a national HIV infection surveillance system to compile the information from smaller regional or local organisms would contribute substantially to our understanding of the epidemiology and evolution of HIV infection.

Adolescent↗
PubMed1998

The role of a stromal cell-derived factor-1 chemokine gene variant in the clinical course of HIV-1 infection.

BACKGROUND: A G-to-A transition in the 3' untranslated region (UTR) of stromal cell-derived factor (SDF)-1 gene (SDF1-3'A) has recently been described, which in the homozygous state was associated with delayed disease progression. OBJECTIVE: To analyse the effect of the SDF-1 polymorphism on AIDS-free survival and survival after AIDS diagnosis, also in relation to viral phenotype. DESIGN: Retrospective longitudinal study among 344 homosexual HIV-1-infected men. RESULTS: A more rapid progression to AIDS (Centers for Disease Control and Prevention 1993 definition) was observed in SDF1-3'A/3'A subjects than in wild-type (SDF1-wt/wt) subjects (relative hazard, 1.75; P = 0.07). Using death as an endpoint, accelerated progression was no longer observed (relative hazard, 0.93; P = 0.84), suggesting a late protective effect of the SDF1-3'A/3'A genotype. Indeed, survival after AIDS diagnosis was significantly delayed in SDF1-3'A/3'A subjects (relative hazard, 0.40; P = 0.02). No effect of the SDF1-3'A/wt genotype on disease progression was observed. Interestingly, a higher frequency of Kaposi's sarcoma was observed as the AIDS-defining event among SDF1-3'A/3'A (40.0%) and SDF1-3'A/wt (30.6%) subjects than in SDF1-wt/wt subjects (17.0%). At the end of the study the total frequency of syncytium-inducing (SI) HIV-1 variants was lower in SDF1-3'A/3'A subjects (22.2%) than in SDF1-3'A/wt (32.5%) and SDF1-wt/wt subjects (40.5%), although not significantly. SDF-1 genotype did not influence the rate of evolution to SI HIV-1. Progression to AIDS after the emergence of SI HIV-1 was accelerated in SDF1-3'A/3'A subjects compared with the SDF1-wt/wt genotypic group (relative hazard, 4.04; P = 0.06). CONCLUSIONS: In our study group, homozygosity for a G-to-A transition in the 3' UTR of SDF-1 is associated with an accelerated progression to AIDS but a subsequent prolonged survival after AIDS diagnosis.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Longitudinal analysis of nef/long terminal repeat-deleted HIV-1 in blood and cerebrospinal fluid of a long-term survivor who developed HIV-associated dementia.

We studied the evolution and compartmentalization of nef/long terminal repeat (nef/LTR)-deleted human immunodeficiency virus type 1 (HIV-1) from a long-term survivor who developed HIV-associated dementia (HIVD). Analysis of sequential blood-derived HIV-1 isolated before and during HIVD revealed a persistent R5X4 phenotype and a progressive loss of nef/LTR sequence; in contrast, HIV-1 present in cerebrospinal fluid during HIVD had an R5 phenotype, distinct nef/LTR sequence of unique deletions and additional nuclear factor- kappa B sites and specificity factor-1 sites, and enhanced transcriptional activity, compared with the blood-derived isolates. Thus, nef/LTR-deleted HIV-1 strains may undergo compartmentalized evolution in long-term survivors and cause neurologic disease.

AIDS Dementia Complex↗
PubMed1989

Morphogenesis, evolution and prognostic significance of lymphatic tissue lesions in HIV infection.

Morphological changes in lymph node biopsies of HIV-infected patients can be classified in four stages, based upon the degree of damage to follicular structures: (1) follicular hyperplasia, (2) follicular lysis, (3) follicular atrophy and (4) follicular and lymphocytic depletion. To define the relative usefulness of morphological, clinical and immunological findings for prognostic purposes, we followed the clinical evolution of 86 biopsied HIV+ patients for a period ranging from 1 to 56 months. A relatively good correlation between histological and clinical findings, at the time of biopsy, was observed. Statistical analysis confirmed the prognostic value of the histological features for clinical deterioration, progression to AIDS and survival. Moreover, histological findings gave more reliable prognostic information than clinical values. Our data suggest that lymph node biopsy can be utilized for prognostic purposes in the evaluation of the progression of the disease and effectiveness of antiviral therapeutic trials.

Acquired Immunodeficiency Syndrome↗
PubMed1992

[Prognostic factors in HIV-infected heroin addicts: a multivariate analysis of nonspecific serological factors in the evolution of the infection].

We present a prognostic analysis of the quantifying of serum levels of beta 2 microglobulin, neopterina, IL-2 soluble receptor and three major classes of immunoglobulins, in a group of 68 heroin-addicts infected by the human immune deficiency virus, type I, clinically assessed for a period of at least three years. High levels of any of these unspecific serologic factors were correlated with the illness progression. Survival curves were generated with the categorized variables, showed a significant decrease on the time interval prior to the diagnosis of AIDS, in the patients with these variables assigned on the higher groups, being neopterine and IgA the more predictive factors when the Cox proportional regression model is applied. We conclude that the quantifying of these unspecific serum factors provides a useful information regarding the clinical evolution of heroin-addicts with HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Evolution of phenotypic memory T cells in HIV-1 infected infants and children.

Infants are reported to be devoid of memory T cells at birth but acquired them with time. A cross-sectional study of peripheral blood mononuclear cells from HIV-infected and uninfected infants and children that bear the CD4R0 antigen was undertaken to describe the development of memory T cells. Linear regression lines derived from the data revealed increasing percentages of memory CD4 and CD8 cells in the uninfected children. Memory CD4 cells in the infected children were detected at a frequency equal to or greater than that seen in uninfected children until 6 months of age but subsequently declined with age. In contrast, memory CD8 cells were found to be significantly increased in HIV-infected children early in life with a rate of increase similar to that seen in the uninfected population. This increase in memory CD8 cells may facilitate the early diagnosis of HIV infection.

CD4-Positive T-Lymphocytes↗
PubMed2006

HIV-1 subtype C in vitro growth and coreceptor utilization.

Human immunodeficiency virus type 1 subtype C (HIV-1C) accounts for about 50% of all HIV infections in the pandemic and is the predominant subtype in the heavily burdened region of southern Africa. HIV-1C possesses unique genetic and phenotypic features that might be associated with biological differences compared to other subtypes. Here, we generated virus isolates from individuals at different stages of HIV-1C infection and investigated the chemokine receptor repertoire that the derived HIV-1C isolates may utilize for entry. Our results show that the R5 phenotype predominates among viruses in Botswana, with a lesser contribution of viruses showing the dualtropic X4R5 phenotype. No viruses of pure X4 phenotype were found, which suggests no discernable evolution of HIV-1C to a monotropic X4 phenotype as the epidemic ages in Botswana. Usage of other coreceptors was rare and apparently insignificant. These results enhance our understanding of HIV-1C biology, with implications for designing and testing therapeutic and prophylactic agents.

Cell Line↗
PubMed2002

Viral evolution and challenges in the development of HIV vaccines.

Potent virus-specific cytotoxic T lymphocyte (CTL) responses elicited by candidate AIDS vaccines have been shown to provide short-term control of viral replication following pathogenic viral challenges in rhesus monkeys. We have recently shown that vaccines that control rather than prevent immunodeficiency virus infections are still subject to immune escape. In particular, viral mutations can develop that result in viral escape from recognition by immunodominant CTL, loss of immune control of viral replication, and clinical disease progression. These data suggest that viral escape from CTL may prove to be a significant limitation of the current generation of CTL-based AIDS vaccines.

AIDS Vaccines↗
PubMed2003

Rapid evolution of the neutralizing antibody response to HIV type 1 infection.

A recombinant virus assay was used to characterize in detail neutralizing antibody responses directed at circulating autologous HIV in plasma. Examining serial plasma specimens in a matrix format, most patients with primary HIV infection rapidly generated significant neutralizing antibody responses to early (0-39 months) autologous viruses, whereas responses to laboratory and heterologous primary strains were often lower and delayed. Plasma virus continually and rapidly evolved to escape neutralization, indicating that neutralizing antibody exerts a level of selective pressure that has been underappreciated based on earlier, less comprehensive characterizations. These data argue that neutralizing antibody responses account for the extensive variation in the envelope gene that is observed in the early months after primary HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Molecular epidemiology of an HIV-1 subtype A subcluster among injection drug users in the Southern Ukraine.

Phylogenetic characterization of primary isolates from 17 HIV-1-infected individuals within a recent epidemic in the city of Odessa, Ukraine was conducted. The isolates were drawn from two time periods, 1993 and 1996. The 1996 isolates coincided with the first apparent expansion of HIV-1 among injection drug users (IDU). Multi-locus phylogenetic analysis indicated that HIV-1 gag, env, tat, and long terminal repeat (LTR) sequences all conformed to the HIV-1 classification of a subcluster within subtype A. There was no evidence for intersubtype recombinants among these isolates. A number of potential signature sequences, particularly within env, were identified in these two time periods, possibly suggesting a selective pressure on viral evolution among IDU. Results of this study are consistent with a recent introduction and subsequent independent evolution of an HIV-1 subtype A subcluster among IDU in the Southern Ukraine. This study demonstrates a congruence of multi-locus phylogenetic analysis, and suggests that non-B genetic subtypes, such as HIV-1 subtype A, may become relevant to the study of IDU transmission in the future.

Amino Acid Sequence↗
PubMed2001

Evolution of cervical abnormalities among women with HIV-1: evidence from surveillance cytology in the women's interagency HIV study.

OBJECTIVE: To determine incidence, progression, and regression rates for abnormal cervical cytology and their correlates among women with HIV. METHODS: In a multicenter prospective cohort study conducted October 1, 1994, through September 30, 1999 at university, public, and private medical centers and clinics, 1639 HIV-seropositive and 452 seronegative women were evaluated every 6 months for up to 5 years using history, cervical cytology, T-cell subsets, and quantitative plasma HIV RNA. Human papillomavirus (HPV) typing at baseline was determined by polymerase chain reaction. Cytology was read using the Bethesda system, with any smear showing at least atypia considered abnormal. Poisson regression identified factors associated with incident cytologic abnormalities whereas logistic regression identified those associated with progression and regression after an abnormality. RESULTS: At least one abnormal smear was found during all of follow-up among 73.0% of HIV-seropositive patients and 42.3% of seronegatives (p <.001). Only 5.9% of seropositives ever developed high-grade lesions, and the proportion with high-grade findings did not rise over time. Incidence of atypical squamous cells of uncertain significance (ASCUS) or more severe lesions among HIV-seropositive patients and seronegative patients was 26.4 and 11.0/100 woman-years (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.9-3.0), whereas that of at least low-grade squamous intraepithelial lesions (SIL) was 8.9 and 2.2/100 (RR, 4.0; CI, 2.6-6.1). HIV status, detection of the presence of human papillomavirus (HPV), CD4 lymphocyte count, and HIV RNA level predicted incidence of abnormal cytology (p <.05); HPV detection and HIV RNA level predicted progression (p <.01); and HPV detection, CD4 lymphocyte count, and HIV RNA level predicted regression (p <.001). Rates of incidence, progression, and regression of abnormal cytology did not differ between HIV seronegative women and seropositive women with CD4 lymphocyte counts >200/mm(3) and HIV RNA levels <4000/ml of similar HPV status. CONCLUSIONS: Although HIV infected women were at high risk for abnormal cytology, high-grade changes were uncommon. HIV status, HPV detection, CD4 lymphocyte count, and HIV RNA level predicted the incidence of cervical cytologic abnormalities. Progression was significantly increased only among the most immunosuppressed women, while regression was significantly reduced in all HIV seropositive women except those with the best controlled HIV disease.

Adult↗
PubMed2005

Inpatient care of the HIV infected patient in the highly active antiretroviral therapy (HAART) era.

The inpatient presentation of the HIV infected patient has changed over the years. From the early years when patients presented with accumulating opportunistic infections that led to an early demise to the HAART era with reports of dramatic decreases in opportunistic infections and improvements in life expectancy, the evolution of inpatient HIV care has been a challenge to the clinician. In the HAART era the presentation of the HIV inpatient has diversified and in many ways is more challenging than the management of the HIV inpatient in the pre-HAART era. We will discuss the changing dynamics of HIV inpatient care from socioeconomic changes to changes in the presentation and reasons for hospitalization.

AIDS-Related Opportunistic Infections↗
PubMed2006

The genetic stability of a conditional live HIV-1 variant can be improved by mutations in the Tet-On regulatory system that restrain evolution.

Live attenuated human immunodeficiency virus type 1 (HIV-1) vaccines are considered unsafe because more quickly replicating pathogenic virus variants may evolve after vaccination. As an alternative vaccine approach, we have previously presented a doxycycline (dox)-dependent HIV-1 variant that was constructed by incorporating the tetracycline-inducible gene expression system (Tet-On system) into the viral genome. Replication of this HIV-rtTA variant is driven by the dox-inducible transcriptional activator rtTA and can be switched on and off at will. A large scale evolution study was performed to test the genetic stability of this conditional live vaccine candidate. In several long term cultures, we selected for HIV-rtTA variants that no longer required dox for replication. These evolved variants acquired a typical amino acid substitution either at position 19 or 37 in the rtTA protein. Both mutations caused rtTA activity and viral replication in the absence of dox. We designed a novel rtTA variant with a higher genetic barrier toward these undesired evolutionary routes. The corresponding HIV-rtTA variant did not lose dox control in long term cultures, demonstrating its improved genetic stability.

AIDS Vaccines↗