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PubMed1999

Short-term follow up of cervical squamous intraepithelial lesions associated with HIV and human papillomavirus infections in Africa.

A prospective study in gynaecology clinics was conducted in Abidjan, Côte d'Ivoire, to assess the short-term evolution of squamous intraepithelial lesions (SILs). Of 94 women with a cytological diagnosis of SIL, 38 were infected with HIV. The average follow-up period after the initial smear was 5 months. Detection of human papillomavirus (HPV) by polymerase chain reaction (PCR) was performed at both the time of enrolment and final follow-up smear. There were 39 cases of persistent SILs. HIV-positive women had a higher percentage of persistent SIL (76%) than HIV-negative women (18%, relative risk (RR)=4.3, 95% confidence interval (CI) = 2.4, 7.7). SILs were more frequent among women infected with HPV at the time of enrolment or with persistent HPV infection, but these associations disappeared after adjusting for HIV serostatus. Spontaneous regression of SILs commonly occurs in HIV-negative African women. HIV-infected women with cervical dyskaryosis require gynaecology follow-up.

Adult↗

PubMed2006

Characterization of HIV-1 envelope gp41 genetic diversity and functional domains following perinatal transmission.

BACKGROUND: HIV-1 envelope gp41 is a transmembrane protein that promotes fusion of the virus with the plasma membrane of the host cells required for virus entry. In addition, gp41 is an important target for the immune response and development of antiviral and vaccine strategies, especially when targeting the highly variable envelope gp120 has not met with resounding success. Mutations in gp41 may affect HIV-1 entry, replication, pathogenesis, and transmission. We, therefore, characterized the molecular properties of gp41, including genetic diversity, functional motifs, and evolutionary dynamics from five mother-infant pairs following perinatal transmission. RESULTS: The gp41 open reading frame (ORF) was maintained with a frequency of 84.17% in five mother-infant pairs' sequences following perinatal transmission. There was a low degree of viral heterogeneity and estimates of genetic diversity in gp41 sequences. Both mother and infant gp41 sequences were under positive selection pressure, as determined by ratios of non-synonymous to synonymous substitutions. Phylogenetic analysis of 157 mother-infant gp41 sequences revealed distinct clusters for each mother-infant pair, suggesting that the epidemiologically linked mother-infant pairs were evolutionarily closer to each other as compared with epidemiologically unlinked sequences. The functional domains of gp41, including fusion peptide, heptad repeats, glycosylation sites and lentiviral lytic peptides were mostly conserved in gp41 sequences analyzed in this study. The CTL recognition epitopes and motifs recognized by fusion inhibitors were also conserved in the five mother-infant pairs. CONCLUSION: The maintenance of an intact envelope gp41 ORF with conserved functional domains and a low degree of genetic variability as well as positive selection pressure for adaptive evolution following perinatal transmission is consistent with an indispensable role of envelope gp41 in HIV-1 replication and pathogenesis.

Adult↗

PubMed2006

Minimization of genetic distances by the consensus, ancestral, and center-of-tree (COT) sequences for HIV-1 variants within an infected individual and the design of reagents to test immune reactivity.

Eliciting maximal immune responses to highly divergent viruses is a challenge and a focus in AIDS vaccine development. Another challenge is to identify the immune correlates of protective immunity. Recent AIDS vaccine design approaches attempt to use reconstructed centralized viral sequences that minimize genetic differences to circulating viruses. Using these approaches, we derive and analyze consensus (CON), ancestral (ANC), and center-of-tree (COT) sequences to represent intra-individual HIV-1 env variants encoding a range of diversities and phylogenetic structures. Each reconstructed sequence significantly minimized genetic distances to extant sequences throughout the first 5 years of infection of an individual. Interestingly, ANC sequences diverged and were not significantly better than extant sequences in minimizing genetic distances at later stages of infection and disease, likely due to the development of a substantially asymmetric phylogeny. COT or CON sequences derived from autologous virus samplings may be useful for increasing the sensitivity of assessments of immune reactivity against HIV.

Amino Acid Sequence↗

PubMed2003

HIV, 'an evolving species'. Roles of cellular activation and co-infections.

Each small variation of the genome of a species can be preserved if it is useful for the survival of the species in a given environment. Within this framework, the finality of the biological cycle of HIV consists in a search for harmony (biological coherence) with man, which is to say a stable condition. Cellular activation appears to be the strategy developed by HIV in order to achieve this coherence. The price of this strategy is the AIDS. The first contact between HIV and immune system appears to determine the subsequent clinical outcome and the future of HIV. Lymphocytic activation varies during the course of the vital cycle of HIV. For each individual, this lymphocytic activation depends on both the HLA repertoire acquired during thymic ontogenesis and the antigenic experience before and after HIV infection. Thus intercurrent infections alter the immune condition of the organism and influence the outcome of HIV. We described a synthetic analysis of the effects of HIV on the surface protein expression and the cellular activation pathways which should provide insights in the evolutionary relationship between HIV and man and should permit to do a more physiological therapeutic approach.

Acquired Immunodeficiency Syndrome↗

PubMed1992

[Estimated biological markers of progression in human immunodeficiency virus infection].

The biological markers for determining as early as possible the progression in the infection by the human immunodeficiency virus (HIV) are very important for the health care of patients, and to adapt their anti-retroviral treatment. Among those, four independent biological markers for predicting a pejorative evolution in the following 36 months are used in medical practice: two specific for HIV, p24 antigenemia and serum titre of antibodies to the p24 core antigen, and two non-HIV specific surrogate markers, the beta 2-microglobulinemia and the absolute number of CD4 T cell in blood. P24 antigenemia corresponds to an active retroviral in vivo replication. The cut off for detection is about 10 pg/ml. It is difficult to detect in black people, and in the asymptomatic or pauci-symptomatic stages of the disease. The apparition or the increase of the serum p24 antigen levels suggest the occurrence of opportunistic infections. P24 antigenemia decreases or disappears during the treatment by zidovudine. The diminution or the disappearance of serum antibodies directed to the p24 core protein are secondary to the deficiency of the humoral immunity, and to an increase of the viral replication, which occur at the late stage of the disease. The diminution or the disappearance of serum antibodies to p24 precede the occurrence of AIDS by several months. The increase of the serum beta 2-microglobulin level is associated with the severity of the disease. In the San Francisco prospective cohort, the progression to AIDS in 36 months was 69% when beta 2-microglobulinemia was more than 5 mg/l, 33% when it was between 3.1 to 5 mg/l, and 12% when it was less than 3 mg/l. The beta 2-microglobulin intra-thecal synthesis level could serve as a marker for the specific HIV encephalitis. The CD4 lymphocyte count constitutes an independent provisional marker for progression to AIDS, probably the most important, but mainly of statistical value. A lymphocyte count of 200 CD4/mm3 is considered as the threshold of full blown AIDS. Beside these classic biological markers, numerous other parameters have been evaluated, without knowing their practical interest. Although the predictive markers for AIDS have a real statistical significance, their interpretation could be difficult or hazardous when applied to a sole individual. In a relatively short delay, the actual biological markers will probably be completed or changed, in the routine medical practice, by the use of direct virological markers evaluating the viral load (plasmatic or cellular viremia).

Antiviral Agents↗

PubMed1990

[Malignant otitis externa and HIV antibodies. A case report].

The AA. inform about the case of a young man, 23, with immunodeficiency (positive HIV antibodies) and malignant otitis externa associated. They recall the etiopathogenesis, the diagnosis, the evolution and the treatment of the disease, pointing out that this case is the first one (published in the ENT bibliography) of malignant otitis-external otitis and HIV linked together.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Acute HIV-1 infection: clinical and biological study of 12 patients.

We observed 12 patients with acute human immunodeficiency virus type 1 (HIV-1) infection. The clinical syndrome was characterized by fever (all cases), generalized lymphadenopathy (11), arthralgias and myalgias (9), sore throat (9), rash (7), splenomegaly (6), and other less frequent signs and symptoms. All patients had a spontaneous resolution of their symptoms within 5-30 days. Anti-HIV-1 serum antibodies, as measured by enzyme immunoassay (EIA) at the onset of clinical illness, were negative in every patient. HIV antigen (p24), on the contrary, was detectable in nine cases. Western blot IgM and IgG analysis was serially performed: IgMs were positive in nine cases and IgGs in three. The CD4+/CD8+ ratio was low in all patients because CD8+ were remarkably increased and CD4+ slightly reduced. A laterocervical lymph nodes biopsy was performed in four patients. The morphological and immunohistological pattern of the acute HIV-1-related lymphadenopathy did not correspond to any of the typical ones. The envelope virus protein gp120/160 was found in interfollicular and follicular lymphocytes, in endothelial cells, and in interdigitating and dendritic reticulum cells. The p17 and p24 core virus proteins were mainly detected in endothelial, interdigitating, and dendritic reticulum cells, but in only a few lymphocytes. The follow-up suggests a rapid evolution to ARC and AIDS in patients showing an acute symptomatic HIV infection.

Acute Disease↗

PubMed2006

Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease.

BACKGROUND: The causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1-V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants. RESULTS: Genetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1-V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differences in vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developed de novo in the infected children, varied but was not predictive of disease progression. CONCLUSION: Our data suggest that neither genetic variation in env, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of the de novo neutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children.

Amino Acid Substitution↗

PubMed2005

Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection.

BACKGROUND: Many antiretroviral-treated human immunodeficiency virus (HIV)-infected patients experience sustained immunologic and virologic benefit despite the presence of multidrug-resistant HIV. We hypothesized that the use of simplified regimens could maintain treatment benefit while preventing viral evolution and reducing drug-related toxicity and costs. METHODS: We conducted a 48-week nonrandomized study of adults with multidrug-resistant HIV type 1 infection. Subjects interrupted protease inhibitor (PI) (n=18), reverse-transcriptase inhibitor (RTI) (n=6), or nonnucleoside RTI (NNRTI) (n=6) treatment. RESULTS: At study entry, subjects had a median reduction in HIV RNA levels of 1.2 log10 copies/mL relative to pretreatment levels. Interruption of PI treatment was associated with stable HIV RNA levels (mean change per week, +0.005 log10 copies/mL; P=.36). PI mutations waned and replicative capacity and HIV RNA levels increased after long-term observation. HIV RNA levels also remained stable in subjects interrupting NNRTI treatment. In contrast, all subjects who interrupted RTI treatment exhibited immediate increases in HIV RNA levels, and most exhibited a subsequent loss of the M184V mutation. CONCLUSIONS: These data indicate that nucleoside analogues often exert continued antiviral activity in the setting of drug-resistance mutations and that both nucleoside analogues and PIs can select for drug-resistance mutations that reduce viral fitness. These observations support the evaluation of treatment strategies aimed at maintaining the treatment benefit of therapy while reducing drug exposure.

Anti-Retroviral Agents↗

PubMed2003

In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells.

The destruction of the immune system by progressive loss of CD4 T cells is the hallmark of AIDS. CCR5-dependent (R5) human immunodeficiency virus type 1 (HIV-1) isolates predominate in the early, asymptomatic stages of HIV-1 infection, while CXCR4-dependent (X4) isolates typically emerge at later stages, frequently coinciding with a rapid decline in CD4 T cells. Lymphocyte killing in vivo primarily occurs through apoptosis, but the importance of apoptosis of HIV-1-infected cells relative to apoptosis of uninfected bystander cells is controversial. Here we show that in human lymphoid tissues ex vivo, apoptosis of uninfected bystander CD4 T cells is a major mechanism of lymphocyte depletion caused by X4 HIV-1 strains but is only a minor mechanism of depletion by R5 strains. Further, X4 HIV-1-induced bystander apoptosis requires the interaction of the viral envelope glycoprotein gp120 with the CXCR4 coreceptor on CD4 T cells. These results emphasize the contribution of bystander apoptosis to HIV-1 cytotoxicity and suggest that in association with a coreceptor switch in HIV disease, T-cell killing evolves from an infection-restricted stage to generalized toxicity that involves a high degree of bystander apoptosis.

Apoptosis↗

PubMed2002

[Castleman's disease in patients infected with HIV].

PURPOSE: Castleman's disease is a polyclonal lymphoplasmacytic and vascular proliferation prominant in lymphoid tissues. It is associated with lymph node enlargement, hepatosplenomegaly and fever. This manifestations could be secondary to hyperproduction of interleukin 6. The prognosis is poor. The opportunistic infections which are characteristic of severe HIV infection worsen the prognosis. Prolonged monochemotherapy with vinblastine or etoposide can control Castleman's disease. CURRENT KNOWLEDGE AND KEY POINTS: Recent advances in human herpesvirus 8 (HHV8) knowledge and its predominance in the forms which are linked to the HIV seropositivity have partly explained the clinical manifestations of Castleman's disease. Indeed, HHV8 produce an homologous interleukin 6, the vIL-6, responsible for lymphoplasmacytic proliferation. The presence of other homologues of human cytokines produced by HHV8 could contribute to lymphoplasmacytosis and to endothelial proliferation. FUTURE AND PROSPECTS: Taking into account this viral origin, alpha interferon could be an alternative in forms which are less progressive. However, antiviral therapy against HHV8 or HIV and the immunitary restoration do not have any influence on the evolution of Castleman's disease, contrary to opportunistic infections.

Castleman Disease↗

PubMed2002

Therapeutic challenges of AIDS-related non-Hodgkin's lymphoma in the United States and East Africa.

Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. As we enter the third decade of the acquired immunodeficiency syndrome (AIDS) epidemic, it is apparent that the evolution of antiretroviral therapy and the emergence of combination antiviral strategies have greatly affected the natural history of HIV infection and its neoplastic complications. For example, there may be a trend for declining incidence of AIDS-related lymphoma in the United States for the first time. However, in regions of the world where the burden of HIV infection is greatest, such as in East Africa, AIDS-related lymphoma is an increasing cause of morbidity and mortality. Treatment of lymphoma has evolved coincident with improvements in antiretroviral therapy. Infusional chemotherapy regimens may offer advantages over other regimens and schedules, but comparative trials have not been done. Clinical trial data are available on which to develop therapeutic strategies to treat this disease in East Africa where pragmatic approaches are needed. Both the differences in manifestations of HIV infection and the inherent difficulties in administering cytotoxic chemotherapy in this part of the world must be taken into consideration in planning therapeutic strategies. Improved understanding of the pathogenesis of HIV infection and lymphoma will likely yield improved therapeutic interventions as well.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10.

HIV-1 Nef is expressed in astrocytes, but a contribution to neuropathogenesis and the development of HIV-associated dementia (HAD) remains uncertain. To determine the neuropathogenic actions of the HIV-1 Nef protein, the brain-derived (YU-2) and blood-derived (NL4-3) Nef proteins were expressed in neural cells using an alphavirus vector, which resulted in astrocyte death (P < 0.001). Supernatants from Nef-expressing astrocytes also caused neuronal death, suggesting the release of neurotoxic molecules by astrocytes. Analysis of pro-inflammatory gene induction in astrocytes expressing Nef revealed increased IP-10 mRNA expression (4000-fold) that was Nef sequence dependent. Recombinant IP-10 caused selective cell death in neurons (P < 0.001) but not astrocytes, and the cytotoxicity of supernatant from astrocytes expressing Nef YU-2 was blocked by an antibody directed against the chemokine receptor CXCR3 (P < 0.001). SCID/NOD mice implanted with a Nef YU-2-expressing vector displayed abnormal motor behavior (P < 0.05), neuroinflammation, and neuronal loss relative to controls. Analysis of mRNA levels in brains from patients with HAD also revealed increased expression of IP-10 (P < 0.05), which was confirmed by immunoreactivity detected principally in astrocytes. Phylogenetic and protein structure analyses of Nef sequences derived from HIV/AIDS patients with and without HAD suggested viral evolution toward a neurotropic Nef protein. These results indicate that HIV-1 Nef contributes to neuropathogenesis by directly causing astrocyte death together with indirect neuronal death through the cytotoxic actions of IP-10 on neurons. Furthermore, Nef molecular diversity was evident in brain tissue among patients with neurological disease and which may influence IP-10 production by astrocytes.

AIDS Dementia Complex↗

PubMed2000

Polymorphism of HIV type 1 gag p7/p1 and p1/p6 cleavage sites: clinical significance and implications for resistance to protease inhibitors.

Amino acid substitutions at HIV-1 Gag p7/p1 and p1/p6 cleavage sites may be selected under antiretroviral pressure or represent natural polymorphisms. Whether changes are associated with specific protease (PR) mutation patterns and different clinical evolution has not been investigated. p7/p1 and p1/p6 cleavage site sequences from sera from 110 patients infected with HIV-1 were compared by regression analysis, using clinical, laboratory, and sequence variables, and the evolution of CD4(+) cell counts and viral load over time. Sixteen of 35 (46%) individuals naive to PR inhibitors (PIs), and 49 of 75 (65%) receiving PI-containing regimens had a p7/p1 and/or p1/p6 cleavage site polymorphism (p = 0.06). A431V and/or L449F were present exclusively among individuals failing PI treatment (17 of 75 [23%] and 3 of 75 [3%], respectively). There was a significant association between A431V and PR M46I,L (OR 13.7; 95% CI 4.2-44.3) and V82A,F,T (OR 8.8; 95% CI 2.7-27.8). Natural polymorphism P453L was strongly associated with the selection of PR I84V (OR 49.5; 95% CI 12-212) and selected against V82 mutation (OR 0.15; 95% CI 0.02-1. 2). After a median followup of 15 months, no polymorphism was associated with parameters of disease progression among individuals failing treatment. Only a limited set of amino acid substitutions can be tolerated at p7/p1 and p1/p6 cleavage sites. A431V is selected in association with specific PR inhibitor mutations. Natural polymorphism P453L might direct the PR resistance pathway through I84V instead of V82 mutation. No short-term clinical impact of cleavage site substitutions was documented.

Capsid↗

PubMed2005

A genetic code Boolean structure. I. The meaning of Boolean deductions.

This paper proposes a genetic code Boolean structure derived from hydrogen bond numbers and chemical types of bases, purines and pyrimidines. It shows that in such Boolean structure, deductions comprise physico-chemical meaning. In particular, codons with adenine as a second base coding to hydrophilic amino acids are not deductible from codons with uracil in the same position, which code to hydrophobic amino acids. Boolean deductions could help us describe the gene evolution process. For instance, most of the reported mutations that confer drug resistance to the HIV protease gene correspond to deductions. What is more, in the human beta-globin gene a similar situation appears where most of the single codon mutations correspond to Boolean deductions from the respective wild-type codon.

Algorithms↗

PubMed1994

Evolution of pathogenic viruses with special reference to the rates of synonymous and nonsynonymous substitutions.

For pathogenic viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human influenza A virus, and human T-cell leukemia virus type I (HTLV-I), the evolutionary features were briefly reviewed with special reference to the rates of synonymous and nonsynonymous substitutions. In particular, these rates were discussed in connection with the neutral theory of molecular evolution. It was common to all the five pathogenic viruses that the rate of synonymous substitution was higher than that of nonsynonymous substitution particularly when the entire gene regions were compared between different isolates. This suggests that the viral proteins are quite conservative to functional and structural changes even though most of these viral genomes are evolving at a speed extraordinarily higher than their host genomes. Thus, this feature is consistent with the neutral theory. However, it is also pointed out that positive selection may be operating on some specific sites such as antigenic sites in order for the pathogenic viruses to escape from the host immune system.

Base Sequence↗

PubMed2006

Stable virulence levels in the HIV epidemic of Switzerland over two decades.

OBJECTIVE: To determine whether the virulence of HIV-1 has been changing since its introduction into Switzerland. DESIGN: A prospective cohort study of HIV-1 infected individuals with well-characterized pre-therapy disease history. METHODS: To minimize the effect of recently imported viruses and ethnicity-associated host factors, the analysis was restricted to the white, north-west-European majority population of the cohort. Virulence was characterized by the decline slope of the CD4 cell count (n = 817 patients), the decline slope of the CD4:CD8 ratio (n = 815 patients) and the viral setpoint (n = 549 patients) in untreated patients with sufficient data points. Linear regression models were used to detect correlations between the date of diagnosis (ranging between 1984 and 2003) and the virulence markers, controlling for gender, exposure category, age and CD4 cell count at entry. RESULTS: We found no correlation between any of the virulence markers and the date of diagnosis. Inspection of short-term trends confirmed that virulence has fluctuated around a stable level over time. CONCLUSIONS: The lack of long-term time trends in the virulence markers indicates that HIV-1 is not evolving towards increasing or decreasing virulence at a perceptible rate. Both highly virulent and attenuated strains have apparently been unable to spread at the population level. This result suggests that either the evolution of virulence may be slow or inhibited due to evolutionary constraints, or HIV-1 may have already evolved to optimal virulence in the human host.

Adult↗

PubMed1990

The evolutionary dynamics of HIV-1 quasispecies and the development of immunodeficiency disease.

This paper presents a theory to explain the development of immunodeficiency disease after a long and variable incubation period of infection with HIV-1. Two assumptions are central to the theory: (1) mutation via reverse transcription during viral replication can generate viral strains resistant to neutralization by antibodies specific to earlier mutants in a particular host; (2) the virus can kill the CD4-positive lymphocytes that play a role in mounting an immunological attack directed at the virus. The theory is examined via the development of a mathematical model which reveals that an increasing number of antigenically distinct viral strains may overwhelm the immune system of the host. As the viral diversity increases beyond a certain level the immune system is unable to suppress the population growth of all the strains simultaneously. The intuitive explanation of this pattern of model behaviour lies in the assumption that each virus can kill CD4-positive lymphocytes that are specific to any of the viral strains, but each lymphocyte only directs immunological attack against a single viral strain.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗