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PubMed1998

Detection of human immunodeficiency virus type 1 (HIV-1) RNA in pools of sera negative for antibodies to HIV-1 and HIV-2.

A total of 234 pools were prepared from 10,692 consecutive serum samples negative for antibodies to human immunodeficiency virus type 1 (HIV-1) and HIV-2 collected at five virological laboratories (average pool size, 45 serum samples). Pools were screened for the presence of HIV-1 RNA by a modified commercial assay (Amplicor HIV-1 Monitor test) which included an additional polyethylene glycol (PEG) precipitation step prior to purification of viral RNA (PEG Amplicor assay). The sensitivity of this assay for HIV-1 RNA detection in individual serum samples within pools matches that of standard commercial assays for individual serum samples, i.e., 500 HIV-1 RNA copies per ml. Five pools were identified as positive, and each one contained one antibody-negative, HIV-1 RNA-positive serum sample, corresponding to an average of 1 infected sample per 2,138 serum samples. Retrospective analysis revealed that the five HIV-1 RNA-positive specimens originated from individuals who had symptomatic primary HIV-1 infection at the time of sample collection and who were also positive for p24 antigenemia. We next assessed the possibility of performing the prepurification step by high-speed centrifugation (50,000 x g for 80 min) of 1.5-ml pools containing 25 microl of 60 individual serum samples, of which only 1 contained HIV-1 RNA (centrifugation Amplicor assay). The sensitivity of this assay also matches the sensitivities of standard commercial assays for HIV-1 RNA detection in individual serum samples. The results demonstrate that both assays with pooled sera can be applied to the screening of large numbers of serum samples in a time- and cost-efficient manner.

Centrifugation↗
PubMed2003

Shifts in cell-associated HIV-1 RNA but not in episomal HIV-1 DNA correlate with new cycles of HIV-1 infection in vivo.

The significance of distinct classes of HIV-1 nucleic acids as correlates of recent HIV-1 replication was assessed in peripheral blood mononuclear cells (PBMC) obtained from 14 patients during 2 weeks of structured interruption of antiretroviral therapy (STI) and 2 weeks of resuming therapy. Levels of HIV RNA in plasma (HIV-RNAplasma) and of unspliced cell-associated HIV-1 RNA (HIV-UsRNAPBMC) were significantly increased as a result of STI, whereas no significant shifts in the levels of 2-LTR episomal HIV-1 DNA (2-LTR circles) and total late HIV-1 reverse transcripts (late-DNA) were observed. Thus, limited viral replication had occurred, which had no effect on the pool size of infected cells in the periphery. Levels of 2-LTR circles did not reflect rapid changes in HIV-1 replication. In contrast, expression of HIV-UsRNAPBMC increased during STI and consequently provides a more sensitive, albeit not absolute cellular marker of ongoing HIV-1 replication.

Anti-HIV Agents↗
PubMed1994

Comprehensive T-cell epitope mapping of HIV-1 env antigens reveals many areas recognized by HIV-1-seropositive and by low-risk HIV-1-seronegative individuals.

Peripheral blood mononuclear cells from 12 asymptomatic human immunodeficiency virus (HIV)-1-seropositive and nine HIV-1-seronegative donors were screened for proliferative T-lymphocyte responses to peptides derived from a consensus sequence of the HIV-1 env gene products from 25 HIV-1 isolates. Two hundred seventy-eight overlapping 17mer peptides, incremented by three residues each, were pooled into groups, each containing eight sequential peptides, for use in proliferation tests. Thirty-eight additional peptides containing variant amino acid residues also were tested. Proliferation data were analyzed using an algorithm that reduced subjective bias and estimated the responding cell frequencies. Peripheral blood mononuclear cells from a majority of donors, regardless of HIV-1 status, recognized peptides within two pools derived from the gp120 sequence and peptides from one pool in gp41. Pool 25 peptides from gp41 (centered around residue 600 of the gp160 consensus sequence) were recognized most frequently. The observed inability to differentiate between responses of HIV-1-seropositive and HIV-1-seronegative individuals implies either a lack of HIV-1 disease-related immunodominant env epitopes or functional abrogation of HIV-1 env-specific T-helper lymphocyte responses soon after infection. The observed proliferation of T lymphocytes from noninfected, low-risk individuals questions the origin of the responses to HIV-1 env-derived peptides and suggest that preexisting, cross-reactive immunity could influence responses to HIV-1.

Adult↗
PubMed2000

Genital tract human immunodeficiency virus type 1 (HIV-1) shedding and inflammation and HIV-1 env diversity in perinatal HIV-1 transmission.

This study sought to identify genital tract characteristics associated with vertical transmission of human immunodeficiency virus type 1 (HIV-1). HIV-1 DNA and RNA, HIV-1 env diversity, and inflammatory cells were quantified in cervicovaginal lavages (CVLs) of 24 women enrolled in the Women and Infants Transmission Study; 7 women transmitted HIV-1 perinatally. Vaginal candidiasis, HIV-1 culture positivity, levels of HIV-1 DNA and cell-free RNA, and HIV-1 env diversity were significantly higher in the CVLs of transmitters. CVL HIV-1 DNA levels correlated with higher levels of inflammatory cells and cell-free HIV-1 RNA. Of subjects with paired blood and CVL specimens, there was more HIV-1 env heterogeneity between blood and CVLs in transmitters than in nontransmitters. In summary, increased HIV-1 shedding is correlated with a more complex population of HIV-1 quasispecies in the genital tracts of parturient women, which may increase the probability that a fetotropic strain is transmitted.

Cervix Uteri↗
PubMed1993

Regulation of HIV production by blood mononuclear cells from HIV-infected donors: I. Lack of correlation between HIV-1 production and T cell activation.

The relationship between production of HIV-1 by peripheral blood mononuclear cells (PBMCs) from HIV-1-infected donors and the level of T cell activation by various stimuli was examined. Stimulation of PBMCs with soluble anti-CD3 antibody or staphylococcal enterotoxin/superantigen (SAg) was found to be 100-1000 times more effective at inducing production of HIV-1 than was stimulation with immobilized anti-CD3 or various other T cell activating agents. However, proliferation of CD4+ T cells and lymphokine production following stimulation with soluble anti-CD3 were less than with immobilized anti-CD3. To determine whether immobilized anti-CD3 stimulated cells may produce a factor(s) that suppresses HIV production, dual-chamber coculture experiments were performed in which soluble and immobilized anti-CD3-stimulated CD8-depleted PBMCs were separated by porous membranes. Stimulation of cells by immobilized anti-CD3 suppressed HIV-1 production by soluble anti-CD3-stimulated cells in the inner chamber, suggesting that diffusible factor(s) are involved in suppressing HIV-1 production. Experiments in which exogenous cytokines were added to cells stimulated with soluble anti-CD3 did not reveal the suppressive factor(s) produced; however, IL-7 was found to markedly increase HIV-1 production. Both T cells and monocytes were found to be required for soluble anti-CD3 to induce high levels of HIV-1 production, suggesting a role for adhesion molecules. Our results thus show that (1) soluble anti-CD3 is a powerful stimulus for HIV production, (2) there is not an absolute correlation between the level of HIV-1 production and T cell activation following stimulation of PBMCs with T cell activating agents, (3) immobilized anti-CD3 stimulation produces a factor that decreases HIV replication, and (4) T cell monocyte interactions are important for production of HIV-1 following stimulation with soluble anti-CD3.

Blood Donors↗
PubMed2006

A nonneutralizing anti-HIV Type 1 antibody turns into a broad neutralizing antibody when expressed on the surface of HIV type 1-susceptible cells. II. Inhibition of HIV type 1 captured and transferred by DC-SIGN.

Previously, we demonstrated that the expression of a nonneutralizing human anti-HIV-1 gp41 scFv on the surface of HIV-1-susceptible cells markedly inhibits HIV-1 replication and HIV-1 envelope-mediated cell-cell fusion. The inhibition is at the level of viral entry, specific for the HIV-1 envelope, and independent of virus tropism. In the previous studies, cell-free viruses of laboratory-adapted HIV-1 strains from subtype B were used to infect human CD4 T cell lines. To further test the effectiveness of this membrane-bound scFv (m-scFv) on HIV-1 infection, in this study, we carried out experiments to determine whether the m-scFv can neutralize infection of primary isolates from various HIV-1 subtypes and whether the m-scFv can neutralize HIV-1 captured and transferred by DC-SIGN on the surface of monocytic cell lines or DCs. We demonstrated that the m-scFv markedly inhibits primary isolates derived from various subtypes and significantly blocks HIV-1 captured and transferred by DC-SIGN on monocytic cell lines and on human DCs. Therefore, a nonneutralizing antibody acts as a broad neutralizing antibody when expressed on the cell surface, which significantly inhibits infection of both cell-free and DC-SIGN-captured and transferred virus. Our studies further point out the potential use of m-scFv as a inhibitor against HIV-1 transmission as well as a tool to dissect the mechanism of HIV-1 entry via DC-SIGN capture and transfer to CD4 T cells.

Antibody Formation↗
PubMed1994

Cross-neutralizing antibodies to HIV-1ANT70 and HIV-1IIIB in sera of African and Belgian HIV-1-infected individuals.

OBJECTIVES: To determine the neutralizing antibody patterns to HIV-1ANT70 (ANT70) and HIV-1IIIB (IIIB) in human sera obtained from HIV-1-infected individuals from different African countries and Belgium. Second, to correlate the presence of neutralizing antibodies in sera and their ability to bind to synthetic peptides derived from eight different HIV-1 V3 loop sequences. DESIGN AND METHODS: Forty sera from Belgium and 88 obtained from seven countries in Africa were tested for their ability to neutralize ANT70 (one of the most genetically divergent HIV-1 isolates documented), and IIIB. Sera found to cross-neutralize both viruses were further challenged with four HIV-1 field isolates. All sera were tested on a panel of V3 loop peptides obtained from different HIV-1 genotypes. RESULTS: Four patterns of sera were identified, including 33 (26%) sera not neutralizing any of the isolates, seven (5%) sera neutralizing only ANT70, 45 (35%) sera neutralizing only IIIB, and 43 (34%) sera cross-neutralizing both isolates. Sera capable of cross-neutralizing both ANT70 and IIIB consistently neutralized other field isolates tested, with a remarkable similarity in neutralizing antibody titre. A significantly higher number of sera cross-neutralizing both ANT70 and IIIB compared with sera lacking neutralizing antibodies, reacted simultaneously in enzyme-linked immunosorbent assays (ELISA) with three or more V3 loop peptides belonging to HIV-1 strains of different genotypes. However, none of the sera cross-neutralizing ANT70 and IIIB were reactive in ELISA with the ANT70 V3 loop peptide. CONCLUSION: These results suggest that despite pronounced genomic variation of the HIV-1ANT70 isolate, there are strongly conserved neutralizing epitopes situated outside the V3 loop that are shared by other HIV-1 isolates. These findings suggest that genetic variation might be surmountable in the design of a polyvalent HIV vaccine, if neutralizing antibodies are found to be correlates of protection in HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Levels of HIV-infected peripheral blood cells remain stable throughout the natural history of HIV-1 infection. Swiss HIV Cohort Study.

OBJECTIVE: To clarify the relationship between the number of provirus-bearing peripheral blood mononuclear cells (PBMC) and HIV-1 disease progression during the natural history of infection. DESIGN: Twenty-four HIV-1-infected subjects with known seroconversion dates and long-term follow-up were retrospectively identified using the Swiss HIV Cohort Database. PBMC specimens from this cohort were retrieved from storage for analysis. METHODS: Infected PBMC equivalents were determined by HIV-1 DNA quantitative competitive (QC)-PCR. The results were analysed with respect to HIV-1 disease stage and compared with a mathematical model of long-term HIV-1 disease progression. RESULTS: PBMC HIV-1 DNA did not correlate with major indices of disease progression, including time following primary infection, time before reaching a CD4 cell count less than 200 x 10(6)/l, and time before death. The number of PBMC harbouring HIV-1 provirus was relatively constant throughout the clinical stages of HIV-1 infection, consistent with simulated data from a mathematical model of long-term HIV-1 infection. We also showed that a biased interpretation of the QC-PCR data may arise when the values are expressed as HIV-1 DNA copies per PBMC or per CD4 cell. CONCLUSIONS: This analysis suggests that levels of provirus-bearing PBMC remain constant during the natural course of HIV-1 infection, whereas plasma virus load typically increases logarithmically during the same period. The hypothesis that plasma virus levels are directly related to the number of infected cells may deserve reconsideration.

Adult↗
PubMed2006

Undiagnosed HIV infection and couple HIV discordance among household members of HIV-infected people receiving antiretroviral therapy in Uganda.

INTRODUCTION: Systematic efforts to identify HIV-infected members and HIV-discordant couples in households of individuals taking antiretroviral therapy (ART) could theoretically reduce HIV transmission and improve ART adherence. METHODS: We enrolled HIV-infected clients of an AIDS support organization in a randomized evaluation of different ART monitoring regimens that offered home-based ART care to them and their clinically eligible household members. At baseline, counselors visited participants' homes and offered voluntary counseling and testing (VCT) to all household members. We assessed uptake, HIV prevalence, HIV discordance, and rate of ART eligibility. RESULTS: Of the 2373 household members, 2348 (99%) accepted VCT. HIV prevalence among household members was 7.5% and varied by age with 9.5% among children aged 0 to 5 years, 2.9% among persons aged 6 to 24 years, and 37.1% among adults aged 25 to 44 years. Of the household members with HIV, 74% had never been previously tested, and 39% of these were clinically eligible for ART. Of the 120 spouses of ART patients that were tested for HIV, 52 (43%) were HIV negative, and of these, 99% had not been previously tested. CONCLUSIONS: Provision of home-based VCT to household members of people initiating ART was well accepted and resulted in the detection of a large number of previously undiagnosed HIV infections and HIV-discordant relationships.

Adolescent↗
PubMed2006

Induction of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses in HIV vaccine trial participants who subsequently acquire HIV-1 infection.

Candidate human immunodeficiency virus type 1 (HIV-1) vaccines designed to elicit T-cell immunity in HIV-1-uninfected persons are under investigation in phase I to III clinical trials. Little is known about how these vaccines impact the immunologic response postinfection in persons who break through despite vaccination. Here, we describe the first comprehensive characterization of HIV-specific T-cell immunity in vaccine study participants following breakthrough HIV-1 infection in comparison to 16 nonvaccinated subjects with primary HIV-1 infection. Whereas none of the 16 breakthrough infections possessed vaccine-induced HIV-1-specific T-cell responses preinfection, 85% of vaccinees and 86% of nonvaccinees with primary HIV-1 infection developed HIV-specific T-cell responses postinfection. Breakthrough subjects' T cells recognized 43 unique HIV-1 T-cell epitopes, of which 8 are newly described, and 25% were present in the vaccine. The frequencies of gamma interferon (IFN-gamma)-secreting cells recognizing epitopes within gene products that were and were not encoded by the vaccine were not different (P = 0.64), which suggests that responses were not anamnestic. Epitopes within Nef and Gag proteins were the most commonly recognized in both vaccinated and nonvaccinated infected subjects. One individual controlled viral replication without antiretroviral therapy and, notably, mounted a novel HIV-specific HLA-C14-restricted Gag LYNTVATL-specific T-cell response. Longitudinally, HIV-specific T cells in this individual were able to secrete IFN-gamma and tumor necrosis factor alpha, as well as proliferate and degranulate in response to their cognate antigenic peptides up to 5 years postinfection. In conclusion, a vaccinee's ability to mount an HIV-specific T-cell response postinfection is not compromised by previous immunization, since the CD8+ T-cell responses postinfection are similar to those seen in vaccine-naïve individuals. Finding an individual who is controlling infection highlights the importance of comprehensive studies of breakthrough infections in vaccine trials to determine whether host genetics/immune responses and/or viral characteristics are responsible for controlling viral replication.

AIDS Vaccines↗
PubMed1990

Ability of anti-HIV agents to inhibit HIV replication in monocyte/macrophages or U937 monocytoid cells under conditions of enhancement by GM-CSF or anti-HIV antibody.

Monocyte/macrophages (M/M) are an important target cell for human immunodeficiency virus (HIV) infection in the body. The study of HIV infection in these cells, however, is rather complicated because they represent a variable population, and because HIV entry and replication in M/M may be markedly influenced by a number of factors. These must be considered in therapeutic approaches to HIV infection. In the present set of experiments, we studied the interaction between certain agents which increase the infection of monocyte/macrophages (M/M) by HIV and two groups of anti-HIV agents: dideoxynucleosides and specific inhibitors of gp120-CD4 binding. We found that the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which markedly enhances HIV replication in M/M, does not affect the activity of recombinant soluble CD4 (sCD4) or OKT4A, two agents which block gp120-CD4 binding. However, it had varying effects on different dideoxynucleosides: GM-CSF increased the net anti-HIV activity of 3'-azido2',3'-dideoxythymidine (AZT), while at the same time it reduced the activity of 2',3'-dideoxycytidine (ddC) and 2',3'-dideoxyinosine (ddI). These effects probably represent an interplay between varying effects of GM-CSF on drug entry and phosphorylation. In additional experiments, we showed that very low concentrations of anti-HIV antibodies could enhance HIV infection of the U937 monocytoid cell line. Interestingly, while this effect has been hypothesized to occur through a CD4-independent mechanism, we found that the anti-HIV activities of both sCD4 and OKT4A were unchanged under conditions of enhancement.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiviral Agents↗
PubMed1992

Potential anti-AIDS naphthalenesulfonic acid derivatives. Synthesis and inhibition of HIV-1 induced cytopathogenesis and HIV-1 and HIV-2 reverse transcriptase activities.

Several naphthalenedi- and trisulfonic acids have been synthesized and evaluated for inhibitory potential against cytopathogenesis and purified recombinant human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptase (RT). The most potent derivative that emerged from the anti-RT study was a small molecule 6 (MW = 840), a dipalmitoylated derivative of 2,7-naphthalenedisulfonic acid. Analog 6 demonstrated 50% inhibitory concentration (IC50) values of 2.42 and 0.86 microM for HIV-1 and HIV-2 RT, respectively. The second most active compound was also a derivative of the same naphthalenedisulfonic acid but contained only one palmitoyl moiety. This compound 9 displayed IC50 values of 4.8 and 3.7 microM for HIV-1 and HIV-2 RT, respectively. Both analogs 6 and 9 are active at noncytotoxic doses, exhibit slightly higher potencies for the RT of HIV-2 over HIV-1, and demonstrate activities superior to the hexasulfonic acid derivative suramin (IC50 values of 9.4 and 15.5 microM for HIV-1 and HIV-2 RT, respectively). In the cytopathogenesis assay, the most active compound is a bis naphthalenedisulfonic acid derivative 17, containing a flexible octamethylene spacer and exhibiting an in vitro therapeutic index of 29.7. Most striking, however, is the influence of the palmitoyl functionality in the naphthalenedisulfonic acid series to confer activity against both HIV-1 and HIV-2 RT.

Enzyme Inhibitors↗
PubMed2000

Pregnancies before and after HIV diagnosis in a european cohort of HIV-infected women. European Study on the Natural History of HIV Infection in Women.

OBJECTIVES: Because most HIV-infected women are of reproductive age, we investigated whether their reproduction planning was affected by their HIV diagnosis. DESIGN: The European women study is a prospective, multicentre cohort of 485 HIV-infected women with a known interval of seroconversion. METHODS: The incidence of pregnancy was measured with person-time methods. Generalized estimating equation analysis was used to determine risk factors for pregnancy and pregnancy outcomes. RESULTS: In 449 women, the age-adjusted incidence of pregnancies decreased from 8.6 before HIV diagnosis to 8.2 and 6.0 per 100 person-years in 0-4 and over 4 years after HIV diagnosis, respectively (P = 0.14). The proportion of induced abortions increased from 42% before to 53% after HIV diagnosis (P < 0.05). The risk of spontaneous abortion did not increase as a result of HIV infection. Since 1995, the proportion of births increased (P = 0.009), whereas that of induced abortions decreased (P = 0.01) compared with earlier years. An increased risk of pregnancy after HIV diagnosis was found in northern and central European women compared with southern European women; there was a lower risk in single women than in women with a steady partner. Of all pregnant women, single women, women between 15 and 25 years of age, and women with multiple partners were at increased risk for induced abortion both before and after HIV diagnosis. CONCLUSION: The incidence of pregnancy decreased with HIV disease progression. Pregnancies after HIV diagnosis appear to be related largely to social and cultural attitudes. The number of induced abortions was high before HIV diagnosis and it significantly increases thereafter.

Abortion, Induced↗
PubMed1997

Diminished HIV-specific CTL activity is associated with lower type 1 and enhanced type 2 responses to HIV-specific peptides during perinatal HIV infection.

The early development of symptoms and the rapid progression of disease in some vertically infected infants are thought to reflect in part the immaturity of their immune systems. We examined the relationship between HIV-specific CTL activity and the profile of cytokine production induced by mAb to CD3 and HIV envelope (env) peptides P18 and T1 in PBMC derived from 0.6- to 3.6-yr-old children with perinatal HIV infection. Cellular immunity against HIV was demonstrated only during early stages of disease, whereas the responses were either undetectable or at background levels in HIV-infected children with rapidly progressing disease and in uninfected children of HIV+ and HIV- mothers. Levels of IL-2 mRNA in anti-CD3 mAb- and env peptide-induced PBMC varied and were increased in the infected children with high frequencies of HIV-specific CTL precursors. Analysis of IFN-gamma and IL-4 production by CD4+ T cell clones obtained from cultures stimulated with anti-CD3 mAb or the env peptides showed an increased proportion of Th2 and Th0 clones in HIV-infected children with lower HIV-specific CTL activity, whereas children with high CTL activity had increased numbers of Th1 clones. The results of these studies suggest that decreases in CTL activity to the virus might be associated with the induction of a type 2 cytokine response. These findings underline the role of cytokines in the generation of HIV-specific CTL responses and may be important for the development of immunomodulatory and vaccine strategies to interrupt vertical transmission of HIV.

Antibodies, Monoclonal↗
PubMed1993

Epitopes for natural antibodies of human immunodeficiency virus (HIV)-negative (normal) and HIV-positive sera are coincident with two key functional sequences of HIV Tat protein.

We have previously shown that IgM antibodies that react with human immunodeficiency virus (HIV) Tat, a regulatory protein essential for viral replication, are present in sera of all normal, HIV-negative individuals and deficient in sera of HIV-positive individuals at progressively greater frequency as diagnosis of AIDS nears. That IgM was designated as a set of natural antibodies, a repertoire of the normal humoral immune system believed to provide early defense against infectious invaders. In the prior study, by means of a series of synthetic peptides representing the amino acid sequence of HIV-1 Tat, one epitope for the IgM natural antibodies was defined within the cysteine-rich domain, shown in cell transfection studies to participate in Tat function. In this study we have defined another epitope, within the basic domain, with which the natural antibodies react. The specific sequence and amino acid residues required for that epitope are coincident with those required for the role of Tat in viral replication. The IgM antibodies reactive with the two epitopes of Tat make up two distinct sets, which, together, account for the total Tat reactivity of both HIV-negative and HIV-positive sera. The striking coincidence of the two epitopes with the two functional sequences of Tat suggests a potential role of those natural antibodies in control of HIV pathogenesis. By inference from the extensive evidence for the presence of extracellular Tat in cultures of HIV-infected cells, Tat may be expected to be present in the circulating plasma of infected people. We propose, therefore, that the Tat-reactive natural antibodies, documented in these studies to be present in the circulating plasma in the pre-AIDS stages of HIV infection, may inhibit cell entry of plasma-borne Tat and thereby curtail HIV propagation. Thus, those natural antibodies may be a host factor for delay in HIV pathogenetic progression.

Amino Acid Sequence↗
PubMed2000

A randomized, double-blind trial of half versus standard dose of zidovudine plus zalcitabine in Thai HIV-1-infected patients (study HIV-NAT 001). HIV Netherlands Australia Thailand Research Collaboration.

BACKGROUND: Triple combination antiretroviral therapy, recommended as standard of care, is unaffordable for much of the developing world. OBJECTIVES: To establish whether half doses of zidovudine (AZT) and zalcitabine (ddC) are as effective as standard doses in a Thai population with lower body weight than Western populations and predominantly infected with HIV-1 subtype E. METHODS: A group of 116 antiretroviral naive patients, with CD4 cell counts 100-500 x 10(6) cells/l, were randomized to: AZT 200 mg three times daily plus ddC 0.75 mg three times daily versus AZT 100 mg three times daily plus ddC 0.375 mg three times daily and followed-up regularly for 48 weeks. RESULTS: The study enrolled 111 patients: 59 men and 52 women, body weight (mean +/- standard deviation) 56.4 +/- 12.3 kg, mean CD4 cell count 324 x 10(6) cells/l, mean HIV RNA 4.7 log10 copies/ml. There were no significant differences between the two groups. Twelve patients discontinued, including two deaths that were unrelated to study medication. No significant differences in adverse events were seen. Week 48 data for the standard dose and half dose arms, respectively, were mean CD4 cell count increases of 52 and 78 x 10(6) cells/l (P = 0.34), mean plasma HIV-1 RNA reduction of 1.4 and 1.1 log10 copies/ml (P = 0.10), HIV RNA of < 400 copies/ml in 52 and 20%[ (P = 0.001). Participants with higher than mean baseline CD8 cell counts (mean 1062 x 10(6) cells/l) showed greater decline in CD8 cells on standard doses. Further analysis showed improved reduction in HIV RNA (P < 0.0001) and in the percentage with undetectable HIV RNA (P = 0.0137) in the standard dose arm, corrected for baseline HIV RNA, which if < 4.75 log10 copies/ml significantly correlated with HIV RNA < 400 copies/ml at week 48. CONCLUSION: At week 48, the proportion with HIV RNA < 400 copies/ml was significantly higher in the standard dose arm; lower baseline HIV RNA correlated with better HIV RNA outcome at 48 weeks. The arms did not differ in CD4 cell response but standard doses correlated with greater CD8 cell decline.

Adult↗
PubMed2000

Diagnosis of primary HIV-1 infection and duration of follow-up after HIV exposure. Karolinska Institute Primary HIV Infection Study Group.

OBJECTIVE: To determine the sensitivity of 33 currently available and seven earlier tests for the detection of HIV or HIV antibody in primary HIV-1 infection, to estimate the duration of the 'window period' and the influence of early initiated antiretroviral treatment (ART). DESIGN: A prospective cohort study of 38 patients with primary HIV-1 infection. ART was initiated at a median time of 13 (range 0-23) days after the onset of symptoms in 10 patients. MAIN OUTCOME MEASURES: The time from infection to onset of symptoms and from onset of symptoms to the appearance of HIV antibody as measured by 36 different tests, and the start and duration of viraemia, as detected by four different tests. RESULTS: The illness appeared 13-15 days after infection in 12 of 15 determinable cases, and seroconversion was detected within 1-2 weeks after the onset of illness by 27 of 30 currently available tests for HIV antibody, in contrast to the 2-7 weeks or more needed by the old tests. HIV RNA appeared during the week preceding the onset of illness and was detected in all subsequent samples, except when ART had been initiated, which also induced a delay of the antibody response. CONCLUSION: Many tests for HIV or HIV antibody can now be employed for an early confirmation of primary HIV infection (PHI). Currently available screening tests proved much more sensitive than older tests, and seroconversion was usually detected within one month after infection. Consequently, in Sweden we now recommend only 3 months of follow-up after most cases of HIV exposure.

Follow-Up Studies↗
PubMed1996

Dual function of a human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte clone: inhibition of HIV replication by noncytolytic mechanisms and lysis of HIV-infected CD4+ cells.

CD8+ T cells may play a beneficial role in human immunodeficiency virus (HIV)-infected patients by two mechanisms. HIV-specific cytotoxic activity and secretion of a soluble mediator(s) that inhibits HIV replication in vitro. Here we characterized both activities mediated by an HIV p24gag-specific cytotoxic T lymphocyte (CTL) CD8+ clone derived from an HIV-infected patient. When the CTL clone was mixed with HIV-infected autologous CD4+ T cells, viral replication was suppressed. This viral inhibition was observed in heterologous CD4+ T cells and when CD8+ and CD4+ populations were separated by a semipermeable membrane, demonstrating the involvement of a diffusible factor(s). The lysis of autologous HIV-infected T cells was also detected. However, HIV suppression was more efficient when CD4+ and CD8+ T cells shared major histocompatibility complex alleles and were in direct contact. Thus, one and the same CD8+ T cell population can mediate both lysis of HIV-infected targets and nonlytic suppression of HIV replication. These results underline the multiple roles of CD8+ T lymphocytes in the suppression of HIV-infected cells.

Amino Acid Sequence↗