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PubMed1990

Influence of pregnancy on human immunodeficiency virus disease.

Over a period of 3 years (mean 16, extremes 3 and 36 months), we compared clinical and laboratory parameters of 128 female, human immunodeficiency virus (HIV)-infected patients, all in clinical stage II or III (CDC classification). 34 patients were pregnant and delivered a viable infant after at least 28 weeks of amenorrhea (group I), 29 patients were pregnant and had a spontaneous or induced abortion during the first or second trimester (group II), and 64 were non-pregnant female control patients (group III). The changes in the clinical stages over time were not statistically significant between the groups. The only laboratory parameters that were significantly higher in group I at the time of the delivery were: leucocyte count (p less than 0.001), lymphocyte count (p less than 0.05), and sedimentation rate (p less than 0.001). These changes are known to be related to pregnancy and not to HIV disease. All other laboratory parameters showed no significant differences within and between the groups. We conclude, that pregnancy--carried to term or interrupted--does not aggravate the natural evolution of HIV infection in clinical stage II and III patients.

Adolescent↗
PubMed2006

Seroreversion in subjects receiving antiretroviral therapy during acute/early HIV infection.

BACKGROUND: We assessed human immunodeficiency virus (HIV) antibody seroreversion among individuals initiating antiretroviral therapy (ART) during acute/early HIV infection and determined whether seroreversion was associated with loss of cytotoxic T lymphocyte responses. METHODS: Subjects in a cohort with acute/early HIV infection (<12 months into infection) who initiated ART within 28 days after study entry and maintained HIV type 1 ribonucleic acid levels of < or =500 copies/mL for >24 weeks were selected. Two clinically available second-generation enzyme immunoassays (EIAs) and a confirmatory Western blot were used to screen subjects for antibody reversion. Those with negative screening test results underwent additional antibody testing, including a third-generation EIA, and were assessed for cytotoxic T lymphocyte responses. RESULTS: Of 87 subjects identified, 12 (14%) had negative antibody test results at the start of ART; all 12 had seroconversion, although 1 had seroconversion only on a third-generation EIA. Of the 87 subjects, 6 (7%) had seroreversion on at least 1 EIA antibody assay while receiving ART during a median follow-up of 90 weeks. The only clinical predictor of seroreversion was a low baseline "detuned" (less sensitive) antibody. Cytotoxic T lymphocyte responses to HIV Gag peptides were detected in 4 of 5 subjects with seroreversion who could be tested. All 5 who had seroreversion who stopped ART experienced virologic rebound and antibody evolution. CONCLUSIONS: HIV antibody seroconversion on second-generation EIA antibody tests may fail to occur when ART is initiated early. Seroreversion was not uncommon among subjects treated early, although cytotoxic T lymphocyte responses to HIV antigens remained detectable in most subjects. Antibody seroreversion did not indicate viral eradication. A third-generation EIA was the most sensitive test for HIV antibodies.

Adult↗
PubMed2005

Impact of human immunodeficiency virus type 1 (HIV-1) genetic diversity on performance of four commercial viral load assays: LCx HIV RNA Quantitative, AMPLICOR HIV-1 MONITOR v1.5, VERSANT HIV-1 RNA 3.0, and NucliSens HIV-1 QT.

Human immunodeficiency virus type 1 (HIV-1) evolution and changing strain distribution present a challenge to nucleic acid-based assays. Reliable patient monitoring of viral loads requires the detection and accurate quantification of genetically diverse HIV-1. A panel of 97 HIV-1-seropositive plasma samples collected from Cameroon, Brazil, and South Africa was used to compare the performance of four commercially available HIV RNA quantitative tests: Abbott LCx HIV RNA Quantitative assay (LCx), Bayer Versant HIV-1 RNA 3.0 (bDNA), Roche AMPLICOR HIV-1 MONITOR v1.5 (Monitor v1.5), and bioMérieux NucliSens HIV-1 QT (NucliSens). The panel included group M, group O, and recombinant viruses based on sequence analysis of gag p24, pol integrase, and env gp41. The LCx HIV assay quantified viral RNA in 97 (100%) of the samples. In comparison, bDNA, Monitor v1.5, and NucliSens quantified viral RNA in 96.9%, 94.8%, and 88.6% of the samples, respectively. The two group O specimens were quantified only by the LCx HIV assay. Analysis of nucleotide mismatches at the primer/probe binding sites for Monitor v1.5, NucliSens, and LCx assays revealed that performance characteristics reflected differences in the level of genetic conservation within the target regions.

Genetic Variation↗
PubMed2006

Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate.

The selective pressure of the competitive protease inhibitors causes both HIV-1 protease and occasionally its substrates to evolve drug resistance. We hypothesize that this occurs particularly in substrates that protrude beyond the substrate envelope and contact residues that mutate in response to a particular protease inhibitor. To validate this hypothesis, we analyzed substrate and protease sequences for covariation. Using the chi2 test, we show a positive correlation between the nelfinavir-resistant D30N/N88D protease mutations and mutations at the p1-p6 cleavage site as compared to the other cleavage sites. Both nelfinavir and the substrate p1-p6 protrude beyond the substrate envelope and contact residue 30, thus possibly making the p1-p6 cleavage site more vulnerable to co-evolution.

Drug Resistance, Viral↗
PubMed2000

Fitness of human immunodeficiency virus type 1 protease inhibitor-selected single mutants.

Human immunodeficiency virus type 1 (HIV-1) evolution under chemotherapeutic selection pressure in vivo involves a complex interplay between an increasing magnitude of drug resistance and changes in viral replicative capacity. To examine the replicative fitness of HIV-1 mutants with single, drug-selected substitutions in protease (PR), we constructed virus that contained the most common mutations in indinavir-selected clinical isolates, PR M46I and V82T, and the most common polymorphic change in drug-naïve patients, PR L63P. These mutants were competed in vitro in the absence of drug against the otherwise isogenic WT virus (NL4-3). Phenotypic drug susceptibility was determined with a recombinant virus assay using a single cycle of virus growth. PR M46I and L63P were as fit as WT. However, PR V82T was out-competed by WT. None of these mutants had appreciable phenotypic resistance to any of the protease inhibitors, including indinavir. The PRV82T mutant was hypersusceptible to saquinavir. Thus, the impaired fitness of the V82T single mutant is consistent with its low frequency in protease inhibitor-naïve patients. The similar fitness of WT (NL4-3), L63P, and M46I is consistent with the common occurrence of L63P in the absence of protease inhibitor-selection pressure, but not with the rare detection of M46I in drug-naïve patients.

Drug Resistance, Microbial↗
PubMed2004

[Renal involvement in the human immunodeficiency virus infection].

BACKGROUND AND OBJECTIVE: Although renal pathologies are becoming an emergent problem in the population infected by the human immunodeficiency virus (HIV), there is very scarce information about the natural course of this problem. The objective of the present study is to describe renal lesions in an autopsy series of HIV-infected patients never treated with antiretroviral therapies. PATIENTS AND METHOD: Autopsy information has been retrospectively retrieved from 61 HIV-infected subjects (mean age, 36,9 [8,4] years; 58,6% drug abusers, 84% males) died in our hospital between 1984 and 1997. None of the patients received antiretroviral therapy. All autopsy and clinical reports were considered, as well as basic analytical parameters about renal function. Renal autopsy samples were specifically reviewed. RESULTS: At the time of the last admission, 9.8% of patients had renal insufficiency, who made up 44.3% of patients having renal insufficiency anytime. Infections were the main cause of death (76%). The majority of patients (93.4%) showed histopathological renal abnormalities, which were highly heterogeneous. Renal lesions were mainly located on the tubules (96.7%) and the interstitium (60.7%). Moreover, glomeruli were affected in 55.7% of patients. Most frequent histopathological diagnosis was acute tubular necrosis (16.4%) and septic nephritic abscesses (16.4%), followed by tubulointerstitial nephritis (9%). HIV-associated nephropathy was present in two patients (3.3%). There were no significant differences when considering the existent of renal failure. CONCLUSIONS: Renal histological abnormalities are frequent in the natural evolution of HIV infection. There is an important heterogeneity of lesions, mainly involving tubules, interstitium and mesangium. The cause of renal lesions is predominantly septic, according to the chief systemic process. It does not exist any relationship between renal analytical parameters and the presence of renal damage.

Adult↗
PubMed1990

HIV serology among Italian male military recruits at entrance and discharge.

To evaluate the usefulness of anti-HIV mass screenings, we examined 662 new military recruits and 1353 soldiers being discharged. None of the former and only one of the latter (0.07%) resulted seropositive on repeated ELISA and Western-blot. For comparison we also report the results of routine anti-HIV antibody testing in our diagnostic laboratory: the highest proportion of seropositive subjects was found among symptomatic patients (79%), followed by haemophiliac patients (31%), drug addicts (24%), sexual partners of seropositive subjects (21%), prisoners (5%) and homosexual men (5%). Health care personnel and prison guards were all negative. These data confirm that in Italy HIV infection is still relatively confined to the classic risk groups. While generalized screening during military service seems to be excessive, periodic sample surveys could be very useful to follow the evolution of HIV epidemiology.

Blotting, Western↗
PubMed1998

Impaired cytokine production by neutrophils isolated from patients with AIDS.

OBJECTIVES: To determine the ability of neutrophils isolated from HIV-seropositive patients to produce proinflammatory cytokines. DESIGN: The in vitro responsiveness of polymorphonuclear neutrophils (PMN) and peripheral blood mononuclear cells (PBMC) to lipopolysaccharide (LPS), used in the presence or absence of interferon (IFN)gamma, was determined in 47 HIV-positive patients with advanced stages of virus infection. METHODS: Cytokines in cell-free supernatants were measured by enzyme-linked immunosorbent assay or radioimmunoassay. RESULTS: Cell-free supernatants from PMN isolated from the peripheral blood of HIV-positive patients and stimulated with LPS contained increased amounts of tumour necrosis factor (TNF)-alpha and interleukin (IL)-8 with respect to supernatants obtained from PMN of normal donors. In contrast, release of IL-1beta and IL-1ra (IL-1 receptor antagonist) in response to LPS, or LPS plus IFNgamma, was found to be lower in PMN from HIV-positive patients than in PMN from controls, but was significant only in the case of IL-1ra. Furthermore, the release of IL-12 induced by LPS or LPS plus IFNgamma did not significantly differ between PMN from HIV-positive patients and healthy donors. Concerning PBMC, the production of TNF-alpha and IL-12 in response to LPS, or LPS plus IFNgamma, was found to be significantly higher in cells isolated from HIV-positive patients, whereas the release of IL-1beta was significantly lower. In the case of IL-8, no statistically significant difference was found between PBMC isolated from HIV-positive patients and healthy donors. CONCLUSIONS: Collectively, the data suggest that in HIV-positive patients with advanced stages of disease, the ability of PMN to produce specific cytokines in response to LPS is significantly altered. Alterations in this ability might contribute to the evolution of HIV disease.

Adolescent↗
PubMed2002

In vitro intersubtype recombinants of human immunodeficiency virus type 1: comparison to recent and circulating in vivo recombinant forms.

The increased prevalence of human immunodeficiency virus type 1 (HIV-1) intersubtype recombinants (ISRs) is shaping HIV-1 evolution throughout the world and will have an impact on both therapeutic and vaccine strategies. This study was designed to generate and compare in vitro ISRs to those isolated from HIV-infected individuals throughout the world. Human peripheral blood mononuclear cells were dually infected with seven pairs of HIV-1 isolates from different subtypes (i.e., A to F). Recombinant crossover sites were mapped to specific regions in the envelope (env) gene by using a cloning-hybridization technique and subtype-specific probes. In vitro intersubtype recombination was at least twofold more frequent in the V1-to-V3 region than in any other env fragment, i.e., C1 to V1, V3 to V5, or V5 to gp41. Sequence and recombination site analyses suggested the C2 env domain as a "hot region" for recombination and selection of replication-competent ISRs during the 15-day incubation. In addition to these regional preferences for env recombination, homopolymeric nucleotide tracts, i.e., sequences known to pause reverse transcriptase and promote template switching, were found in most in vitro crossover sites. ISRs, originating from recent dual infections and limited transmission events, partly retained this in vitro regional or sequence preference for recombination sites. However, a shift to crossover sites flanking the gp120-coding sequence was evident in the stable circulating recombinant forms of HIV-1. Based on these findings, HIV-1 recombinants generated from these dual infections may be used as a model for in vivo intersubtype recombination and for the design of various diagnostic assays and vaccine constructs.

Base Sequence↗
PubMed1996

HIV-1 genetic diversity.

BACKGROUND: HIV-1 evolves by rapid mutation and by recombination, both processes actively contributing to its genetic diversity. Most of the multiple genetic subtypes and intersubtype recombinations of HIV-1 that comprise the global pandemic have not been characterized by full genome sequencing. METHODS: DNA from primary virus cultures on donor peripheral blood mononuclear cells was used as template for long polymerase chain reaction amplification, molecular cloning, and automated sequencing of virtually full-length HIV-1 genomes from subtypes A, C, E, G and A/D recombinant forms. Standard phylogenetic analysis methods were employed, and some were modified for the detection and mapping of recombinant breakpoints. RESULTS: Subtypes A, B, C and D are largely, if not entirely, distinguishable throughout the genome and show no clear evidence of intersubtype recombination. In contrast, all available sequences of subtypes E and G are recombinant with subtype A. Full-length sequences of subtypes F, H, I and J are still unavailable. Subtype E and G, and some A/D recombinant HIV, have retained the cytoplasmic domain of gp41 from subtype A. Some recombinants possess the matrix and core of one subtype and the outer envelope of another, resembling pseudotypes. Certain pairs of subtypes may have recombined more often than others. CONCLUSION: Recombinant HIV-1 have already established a global reservoir and are largely responsible for the rapidly expanding subtype E epidemic in Southeast Asia. Recombination may have played a key role in the evolution of HIV-1 and the geographic intermixing of subtypes, which is increasing, may foster the emergence of a even greater variety of recombinant strains.

DNA, Viral↗
PubMed2004

Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection.

Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8(+) T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.

Amino Acid Sequence↗
PubMed2001

Modelling the natural history of HIV infection in individuals and its epidemiological implications.

The variation of viraemia in the natural course of HIV infection is expected to have major influence on the probability of transmission and, consequently, on the epidemiology of HIV/AIDS. In this paper we propose a model which takes into account the time evolution of HIV viraemia (measured as HIV-RNA copies per ml of blood) in an infected individual and its impact on the threshold for the establishment of an endemic level, and mainly on the relative contribution of each of the clinical phases of the infection to the total transmission of HIV per infected individual. We consider that an infected individual passes through three phases of viraemia. The first phase, which lasts for 6-7 weeks, is characterized by very high viraemia. In the second phase, which lasts about 10 years, the viraemia is much lower, increasing again in the last phase, which lasts up to two years, and ends in full-blown AIDS. We show that the relative contribution of each phase to the total transmission of HIV is very sensitive to the model we assume for the dependence of the transmissibility of HIV on the viral load. For instance, if we assume that transmissibility is proportional to the decimal logarithm of viraemia, then the second phase predominates always. Due to the epidemiological importance of this fact, it is clear that further improvement on virological research to better understand the dependence of HIV transmissibility on the viral concentration in biological fluids is necessary.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Coreceptor usage of HIV-1 isolates representing different genetic subtypes obtained from pregnant Cameroonian women. European Network for In Utero Transmission of HIV-1.

In this study, coreceptor usage of HIV-1 other than subtype B in relation to HIV-1 transmission from mother to child was investigated. Repeated sampling of 42 HIV-1-seropositive, asymptomatic women in Cameroon during the second and third trimesters of pregnancy, at delivery, and 6 months postpartum were performed. Env subtyping was carried out from uncultured peripheral blood mononuclear cells (PBMCs) by heteroduplex mobility assay and, whenever necessary, by DNA sequencing. Virus isolates were tested for coreceptor usage on human cell lines-U87.CD4 and GHOST(3)-engineered to express stably CD4 and the chemokine receptors CCR1, CCR2b, CCR3, CCR5, or CXCR4, or the orphan receptors BOB/gpr15 or Bonzo/STRL33/TYMSTR. Transmission rate was 11.9%. Viruses were predominantly envelope subtype A and used CCR5 as coreceptor and, surprisingly, 4 of 28 (14.2%) isolates from mothers and 1 of 3 isolates from children used the orphan receptor Bonzo as well. In 2 transmitting mothers from whom sequential HIV-1 isolates were available, viral coreceptor usage evolved from CCR5 monotropic to CCR5/Bonzo dual tropic during pregnancy, and in 1 case transmission of this virus could be documented. Our data suggest that evolution of HIV-1 coreceptor usage to dual (or multi-) tropism may occur during pregnancy.

Cameroon↗
PubMed2003

The molecular epidemiology of HIV-1 in South and East Asia.

Foremost amongst human pathogens, the human immunodeficiency virus (HIV) exhibits a great genetic variability. The resultant fluidity of HIV enzymatic proteins allows them to remain functional whilst simultaneously evading immune surrveillance and antiretroviral therapy. This very variability, however, has been turned to powerful advantage in the study of the movement and evolution of HIV strains within and between human populations. Molecular analyses that estimate the relatedness between viral isolates, conducted in tandem with epidemiological studies, provide a new clarity of insight into the modes and routes of HIV transmission and epidemic spread. In this paper the principles underlying the molecular study of HIV and the achievements of this new field of epidemiology in southern and eastern Asia are reviewed.

Asia, Southeastern↗
PubMed2002

Recent evolutionary history of human immunodeficiency virus type 1 subtype B: reconstruction of epidemic onset based on sequence distances to the common ancestor.

We obtained and studied HIV-1 sequences with a known sampling year from three outbreaks of the HIV-1 epidemic: 141 env V3 (270 nt) sampled between 1984 and 1992 and 117 pol prot/RT (804 nt) sequences sampled between 1986 and 1999 from Dutch homosexual men and injecting drug users (IDUs), as well as 77 env V3 sequences sampled between 1983 and 1994 in the United States. Since retrospective serological and/or epidemiological data on these populations are available, providing estimates of the dates of the onset of the HIV-1 epidemics, we had the opportunity to test different phylogenetic models for their accuracy in deriving the recent evolutionary history of HIV-1 subtype B and the onset date of the HIV-1 epidemic. We observed that, in any given year, individual sequences vary widely in their distances to the common ancestor, and sequences close to the ancestors were found decades after the onset of the epidemic. Nevertheless, the mean evolutionary distances of virus strains to ancestors were increasing significantly during the course of the studied epidemics, which indicates that the molecular clock is operational in the recent evolution of HIV-1. When the relationship between the sampling years of sequences and their nucleotide distances to the common ancestor was extrapolated to the past, analysis of pol sequences provided accurate estimates of the onset years of the epidemics, whereas analysis of V3 sequences by the maximum-likelihood or neighbor-joining methods led to an overestimation of the age of the epidemics. Separate analysis of nonsynonymous and synonymous distances revealed that this overestimation results from nonsynonymous substitutions, whose numbers were not increasing significantly in all three virus populations over the observation period. In contrast, analysis of synonymous env V3 distances provided accurate estimates of the onset years for the outbreaks we studied.

Biological Evolution↗
PubMed2004

HIV-resistance to viral entry inhibitors.

An increasing number of human immunodeficiency virus (HIV)-infected patients have detectable viraemia despite treatment with multiple-drug combinations or have developed resistance to all available classes of antiretroviral therapy. HIV entry has become an important pharmacological target. Enfuvirtide is the first HIV entry inhibitor to be approved for the treatment of drug-experienced patients but several other agents are progressing through preclinical and clinical trials. However, because different entry inhibitors target different parts of the entry process their combined effects could be synergistic or generate different distinct profiles of drug-resistance. The HIV envelope glycoprotein that drives HIV entry is highly variable. Its plasticity allows HIV to escape the immune system and its variability is associated with HIV tropism, fitness and replicative capacity. Thus, mutations that confer resistance to entry inhibitors will modify these parameters. Therapeutic strategies that aim at blocking virus entry may also be used to alter the natural evolution of HIV in an unprecedented way. Here, we will describe the structure and function of the envelope glycoprotein complex that constitute the basis for the emergence of resistance to HIV entry inhibitors, review those HIV entry inhibitors for which drug-resistance has been evaluated and discuss the interplay between viral resistance to inhibitors of HIV entry and the pathogenicity of HIV and AIDS.

Amino Acid Sequence↗
PubMed1997

Lymphomas associated with HIV infection.

Lymphomagenesis in HIV positive patients is a complex phenomenon not yet completely understood (Karp and Broder, 1992). The great majority of NHL are of the B cell type. Burkitt lymphoma seems to develop early during the evolution of HIV infection in patients with a CD4 count above 200/microliter. MYC is rearranged in the majority of the cases. EBV latent infection is observed in 30-45%. EBV status is characterized by a negativity for EBNA2 and LMP1 The main sites of the tumour are the lymph node and the bone marrow. Diffuse large cell lymphomas, mostly represented by immunoblastic lymphomas with plasmacytoid differentiation and by centroblastic lymphomas rich in immunoblasts, are a late event in HIV infection, in patients with a low CD4 count (often below 50/microliter). The prognosis is worse than in Burkitt and Burkitt like lymphoma. MYC is rearranged in about 30-40% of the cases, whereas more than 70% are EBV positive. EBV status is characterized by a positivity for both EBNA2 and LMP1. B type ALC lymphomas are more frequently associated with EBV than in the general population and exhibit the same EBV status as diffuse large cell lymphomas. HD occurs at any stage of HIV infection. The majority of patients are in clinical stage III or IV at the time of diagnosis, and HIV associated HD shows a more aggressive course than non-HIV HD. Many cases remain difficult to classify; instead, the immunophenotype of neoplastic cells is similar to that in HD occurring in the general population. Histiocytes and epithelioid cells are even more numerous than T lymphocytes, and the CD4:CD8 ratio is low. Neoplastic cells are EBV positive in most or all cases, although they are consistently HIV negative by in situ hybridization. Lymphomagenesis seems to be very complex, with multiple agents acting together or successively. EBV, other viruses, rearrangement of various genes and production of cytokines all seem to have major roles in addition to immune deficiency.

Humans↗