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PubMed1994

Mycobacterium avium infection in HIV-1-infected subjects increases monokine secretion and is associated with enhanced viral load and diminished immune response to viral antigens.

The complex interaction between HIV-1 infection and Mycobacterium avium was studied. Viral burden was assessed, as well as immune response to HIV-1 in the context of Myco. avium infections. We also examined serum cytokine levels and cytokine release by blood mononuclear cells in HIV-1-infected subjects, infected or not with Myco. avium. Undetectable serum levels of IL-1, tumour necrosis factor-alpha (TNF-alpha) and IL-6 were found in normal controls and in groups I, II and III of HIV-1-infected subjects. Moderate levels of TNF-alpha, IL-1 and IL-6 were found in the sera of group IV patients. When group IV was subdivided into subjects with and without Myco. avium infections, subjects with Myco, avium infections were shown to have higher serum levels of TNF-alpha, IL-1 beta and IL-6 than those with other infections. Blood mononuclear cells from controls and HIV subjects were stimulated with bacterial lipopolysaccharide, and cytokine levels assessed. Cells from group II patients were shown to secrete normal levels of TNF-alpha and IL-6, and lower levels of IL-1 beta; group III subjects released higher levels of IL-6. Patients in group IV had blood cells that released elevated levels of IL-6 and TNF-alpha, and lower levels of IL-1 beta. Group IV subjects with Myco. avium infections had blood cells that released higher levels of TNF-alpha, IL-6 and IL-1 than group IV subjects with other infections. Assessment of viral burden in cells of HIV-1-infected subjects revealed that Myco. avium-infected subjects had a higher level of virus burden and a lower level of lymphoproliferative response to an inactivated gp120-depleted HIV-1 antigen than AIDS subjects with other infections. These data suggest that Myco. avium infections in HIV-1-infected subjects hasten the progression of viral disease, enhance cytokine release and contribute to the anergy to viral antigens.

AIDS-Related Opportunistic Infections↗

PubMed2001

Prevalence of persistent asymptomatic proteinuria in HIV-infected outpatients and lack of correlation with viral load.

AIM: Human immunodeficiency virus-associated nephropathy (HIVAN) is projected to be a leading cause of end-stage renal disease (ESRD) in young African American men in the new millennium. Little is known about the early natural history of the disease, including the prevalence of asymptomatic nephropathy. The primary aim of this study was to define the prevalence of persistent asymptomatic proteinuria in a contemporary, ambulatory human immunodeficiency virus- (HIV) infected population. The secondary aim was to correlate the presence of persistent proteinuria with measures of HIV disease. METHODS: Using a readily available screening tool, the urine dipstick, we determined the prevalence of persistent asymptomatic proteinuria in the outpatient VA Connecticut (VA CT) Healthcare System West Haven HIV Clinic population. We compared the presence of persistent proteinuria with measures of HIV viral disease. RESULTS: The prevalence of persistent asymptomatic proteinuria was 14% (7 of 49 patients). The presence of persistent proteinuria was not correlated with viral load. CONCLUSIONS: A significant prevalence of occult renal disease exists in the asymptomatic HIV-seropositive outpatient population and is not correlated with viral load.

AIDS-Associated Nephropathy↗

PubMed2000

Sustained viral response is rarely achieved in patients with high viral load of HCV RNA by excessive interferon therapy.

Adequate dosing of interferon (IFN) and its cost-effectiveness for sustained virological response were evaluated in relation to viral load and subtype. Prospective analysis of IFN therapy on 326 patients with chronic hepatitis C free from cirrhosis was performed using 9 or 6 million unit (MU) of IFN for six months daily and/or three times a week. Sustained virological response was achieved in 50-94% of patients with < or =2 x 10(4) copies/ml (competitive RT-PCR) or <100 x 10(3) copies/ml (Amplicor monitor) of HCV RNA by 468-1206 MU of IFN, but response was only 0-25% of the patients with > or =2 x 10(5.5) copies/ml (competitive RT-PCR) or >200 x 10(3) copies/ml (Amplicor monitor), even with 468-1206 MU of IFN. A high sustained rate was demonstrated in patients with 100-200 x 10(3) copies/ml of HCV RNA by 901-1206 MU of IFN, in comparison to that with < or =900 MU of IFN. Multivariate analysis showed that IFN dose had a significant value for the efficacy of IFN therapy in patients presenting 100-200 x 10(3) copies/ml of HCV RNA. Cost efficacy analysis indicated that it cost approximately $10,000, $26,000, and $50,000-227,000 for one person-viral eradication in the patients with <100, 100-200, and >200 x 10(3) copies/ml, respectively. High-dose IFN is only cost effective in patients with intermediate viral loads, and IFN therapy could be recommended in patients with <200 x 10(3) copies/ml of HCV RNA.

Adolescent↗

PubMed2002

The efficacy of a herbal medicine (Mao-to) in combination with intravenous natural interferon-beta for patients with chronic hepatitis C, genotype 1b and high viral load: a pilot study.

Patients with chronic hepatitis C, with a high serum viral load (> or = 1 Meq/ml) and genotype 1b seem to be resistant to interferon (IFN) therapy. To evaluate the efficacy of a herbal medicine (Mao-to) in combination with natural IFN-beta for the treatment of these patients, eighteen Japanese patients were enrolled in this study. Every patient received 6 million units (MU) of IFN-beta intravenously daily for 8 weeks. Mao-to was given orally 3-4 times a day during the IFN-beta administration, Sixteen of the 18 patients (89%) became negative for serum HCV RNA at the end of treatment, but only 2 of them (11%) remained negative for the virus RNA at 6 months of follow-up. Serum ALT levels normalized in 17 patients (94%) at 2 weeks of follow-up after the cessation of therapy, and 11 patients (61%) retained normal ALT levels for more than 6 months of follow-up. This rate of biochemical response was high as compared with that of therapy with IFN-beta alone (19%) in the largest IFN-beta trial in Japan. Serum hyaluronic acid levels were decreased significantly from 147.0 +/- 110.5 ng/ml to 77.4 +/- 67.4 ng/ml in the sustained biochemical response group (P = 0.003). None of the patients needed to interrupt therapy because of side effects of IFN-beta. Thus, Mao-to administration together with IFN-beta treatment could increase the sustained biochemical response rate, and reduce liver fibrosis.

Adult↗

PubMed2000

High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients.

Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with human herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma human IL-6 and IL-10 levels. Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.

Adult↗

PubMed2005

Inhibition of HIV-1-specific T-cells and increase of viral load during immunosuppressive treatment in an HIV-1 infected patient with Chlamydia trachomatis induced arthritis.

BACKGROUND: Studies in HIV-1 infected long-term non-progressors could demonstrate a strong HIV-1-specific CTL response, but it is difficult to prove that this strong CTL response actually is the cause of the efficient control of HIV-1 and not the consequence of low HIV-1 replication in these patients. OBJECTIVE: Studies of HIV-1-specific immunity and viral replication in patients undergoing immunosuppressive therapy provide important opportunities to understand the role of HIV-1-specific T-cells. RESULTS: In this report we describe an HLA B27 positive patient with normal CD4 counts and a low viral load of 200 copies/ml without antiretroviral therapy who exhibited a very strong HIV-1-specific CTL response. He had to be treated with steroids, NSAIDS and hydroxchloroquine because of a severe inflammatory reactive arthritis triggered by an acute Chlamydia trachomatis infection. Analysis of HIV-1 specific T-cells by gamma-IFN-ELISPOT revealed a high frequency of HIV-1 gag-specific CTL both in blood and synovial fluid, whereas gag-specific CD4-cells could be detected only in the peripheral blood. Further analysis revealed that the gag-specific T-cells were predominantly targeting the HLA B27-restricted CTL epitope KRWIILGLNK (KK10). Immunosuppressive therapy by prednisone was associated with a moderate increase of HIV-1 viremia and a decrease both in the number and in the gamma-IFN production of KK10-specific CTL indicating that inhibition of CTL function contributed to the increase of viral load. CONCLUSIONS: This study is suggesting that HIV-1 specific CTL play an important role in the control of HIV-1, at least in this patient. Inhibition of CTL function by immunosuppressive therapy with prednisone may enhance viral replication. In addition, we could demonstrate for the first time the migration of HIV-1 specific T-cells into the synovial fluid.

Adult↗

PubMed1996

Serum HCV RNA levels assessed by quantitative NASBA: stability of viral load over time, and lack of correlation with liver disease. The Trent HCV Study Group.

BACKGROUND/AIMS: We used the hepatitis C virus quantitative NASBA technique to evaluate the stability of viral load within individuals with chronic hepatitis C, to determine the range of viraemic load between individuals, and to assess the usefulness of hepatitis C virus RNA quantitation in predicting the severity of underlying hepatitis C virus-induced liver disease. METHODS: Hepatitis C virus RNA was determined, using the quantitative NASBA assay, in multiple serum samples from 11 individuals with chronic hepatitis C over an average time period of 11 months (range = 3-23 months), and in single serum samples from a further 10 individuals. RESULTS: In 10/11 individuals the hepatitis C virus RNA titres were within one log10 copies/ml of each other during this time period. In the eleventh, there was a rise of 1.36 log10 copies/ml in two serum samples taken 8 months apart. The viraemic load varied by 2.79 log10 copies/ml serum between individuals. There were no correlations between mean RNA levels and total biopsy scores (either Knodell or Sheffield scores), or the individual components of the biopsy scoring systems, except the sinusoidal infiltration component of the Sheffield score. There was also no difference in viral RNA levels between those infected with type 1 as compared to type 3 virus, with a mean level in both groups of 7.2 log10 copies/ml. CONCLUSIONS: Hepatitis C virus serum RNA level is stable within individuals within the studied time period. Viral load varies between infected individuals but is not a useful prognostic indicator of the severity of virus-induced liver disease.

Adult↗

PubMed2001

The role of viral load determination for the management of human immunodeficiency virus, hepatitis B virus and hepatitis C virus infection.

During the last 5 years, considerable scientific and financial efforts have been made in the development of quantitative nucleic acid detection technology. For detection of human immunodeficiency virus (HIV), quantitative culture is time consuming, cumbersome and requires appropriate laboratory safety equipment. Quantitative determination of p24 antigen by enzyme immunoassay is of limited value due to its relatively poor sensitivity. Therefore, quantitative determination of viral load using nucleic acid amplification techniques is the most accurate, prognostic marker for HIV type 1 infection, independently of the CD4+ cell count. Hepatitis B virus (HBV) is not cultivable in vitro. Serological assays allow an accurate diagnosis and follow-up of acute or chronic infection. Quantification of HBV DNA is used for the monitoring of antiviral therapy, determination of infectivity and for resolution of unclear serological profiles, e.g. isolated anti-HBc reactivity, as well as for patients in which HBV mutants are suspected. Hepatitis C virus (HCV) can only be detected by molecular based assays because no cell culture system, which permits a reliable isolation of clinical specimens, is currently available. Furthermore, early diagnosis and follow-up of infection cannot be achieved with antibody serology. The prognostic relevance of quantitative HCV RNA determination is of limited value for the long-term prognosis of chronic hepatitis C. However, viral load may predict the outcome of antiviral therapy. Genetic diversity is another challenge for HCV RNA quantification.

HIV Infections↗

PubMed2000

Course of viral load throughout HIV-1 infection.

HIV-1 RNA levels are routinely monitored as part of patient management. However, little is known about the course of HIV-1 RNA levels over the entire period of infection. The aim of this study was to investigate the course of HIV-1 RNA levels in a cohort of men with hemophilia who were observed for up to 17 years after HIV-1 seroconversion, and to assess the risk of HIV disease progression at any HIV-1 RNA level. Viral loads were measured on annual stored serum samples in 107 men with hemophilia A using the Roche Amplicor Monitor assay with non-B primers. On average, HIV-1 RNA levels increased significantly by 0.11 log10 per year over the course of HIV infection. This rate of increase was significantly faster in those who developed AIDS or died over the subsequent 12 to 17 year period, and in those who were older at HIV- 1 seroconversion. The risk of developing AIDS and death remained low when the HIV-1 RNA level was below 4 log10 copies/ml, but increased rapidly thereafter, supporting current guidelines for the initiation of antiretroviral therapy after the viral load has exceeded this level.

CD4 Lymphocyte Count↗

PubMed2005

Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-1 nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption.

The safety and immunogenicity of an HIV-1 nef-expressing modified vaccinia virus Ankara (MVA) was investigated in 14 HIV-1-positive patients (CD4 >400/microl) on highly active antiretroviral therapy (HAART). Patients were vaccinated at weeks 0, 4 and 16, followed by interruption of HAART at week 18. MVA-nef was well-tolerated except for local reactions, with only mild systemic side effects reported in a few patients. Vaccination with MVA-nef was associated with recognition of new HIV-1 T-cell epitopes (cytotoxic T-lymphocyte epitopes in 9/14 patients, CD4 epitope/recombinant Nef protein in 2/14) and an increase in CD4+ and CD8+ T cells. All patients had been vaccinated against smallpox and a strong T-cell and antibody response to MVA was induced in all patients. After interruption of HAART, viral load rebounded in all patients, but after a median time of 36 (4-76) weeks in 9/14 patients, viraemia remained below the pre-HAART viral load and CD4 counts stayed above the pre-HAART levels. While six patients have remained off therapy for a median time of 64 (57-76) weeks, HAART was resumed in 8/14 patients after a median treatment interruption time of 15 (4-38) weeks. This study has demonstrated that MVA-nef is safe and immunogenic in HIV-1-infected subjects and has provided encouraging data on the potential of therapeutic vaccinations.

AIDS Vaccines↗

PubMed2005

BKV-DNA and JCV-DNA co-quantification assay to evaluate viral load in urine and serum.

Infections from human polyomaviruses BK and JC (BKV and JCV) occur independently, but concomitant infections and the simultaneous persistence of both viruses have been observed in renal transplant recipients. Several studies have disclosed a correlation between BKV and interstitial nephritis in renal transplant recipients, and an association between JCV and some cases of nephropathy has recently been hypothesized. This article describes the development of a semiquantitative-nested polymerase chain reaction (PCR) assay to simultaneously detect BKV and JCV viral load in urine and serum. The first-round amplification step uses primers that amplify a 385-bp DNA fragment from the "large T antigen" region of both viruses. Samples testing positive in the first step are then run in the second step. In the second-round amplification, different inner primers are used to separately quantify BKV-DNA and/or JCV-DNA. The assay offers several advantages including: (1) rapid submission of clinical samples to screening; (2) verification of the absence of Taq polymerase inhibitors with the use of an internal control; (3) a sensitivity threshold of 10 copies/reaction; and (4) assay running is less labor intensive, cheap, and easy to perform. The assay may be easily used to monitor viral loads versus baseline levels in urine and serum samples from renal transplant recipients to detect those at risk of BKV- or JCV-related nephropathy, and to monitor their response to immunosuppression reduction therapy if it occurs.

BK Virus↗

PubMed2002

Underevaluation of HIV-1 plasma viral load by a commercially available assay in a cluster of patients infected with HIV-1 A/G circulating recombinant form (CRF02).

The authors studied the correlation and agreement of commercially available assays in detection and quantification of the HIV-1 intersubtype A/G circulating recombinant form CRF02. The assays under comparison were Bayer Versant HIV-1 RNA, version 3.0; Roche Amplicor HIV-1 Monitor, version 1.5 (standard procedure); and Organon Teknika NucliSens HIV-1 RNA QT. Plasma samples from 114 patients infected with CRF02 were tested by the three assays under standard conditions. Although correlation among the assays was high and statistically significant for subtype B and CRF02, in the latter instance, NucliSens measured average viral load values (3.29 +/- 0.71 log(10) copies/mL) about 4 and >8 times lower than those obtained by Versant (3.90 +/- 0.90 log(10) copies/mL) and Amplicor (4.22 +/- 1.05 log(10) copies/mL), respectively. Furthermore, in a statistically significant percentage of CRF02-harboring samples, NucliSens produced viral load values undetectable or 1 log(10) lower than those obtained in Versant and Amplicor assays. Altogether, these data underline a low performance of NucliSens in detecting and quantifying viremia in plasma samples harboring the CRF02. These results are potentially important as global distribution of new HIV-1 subtypes is expanding, and recombinant strains, particularly CRF02, are emerging and becoming highly prevalent.

Adult↗

PubMed2000

Oral mucosal lesions and HIV viral load in the Women's Interagency HIV Study (WIHS).

The prevalence of oral lesions was assessed in a five-center subset of the Women's Interagency HIV Study (WIHS) and correlated with other features of HIV disease. Oral examinations were performed by dental examiners on 729 women (577 HIV-positive and 152 HIV-negative) during baseline examination. Significant differences between the groups were found for the following oral lesions: pseudomembranous candidiasis, 6.1% and 2.0%, respectively; erythematous candidiasis, 6.41% and 0.7%, respectively; all oral candidiasis, pseudomembranous and/or erythematous, 13.7% and 3.3%, respectively. Hairy leukoplakia was observed in 6.1% of HIV-positive women. No significant differences were found for recurrent aphthous ulcers, herpes simplex lesions, or papillomas. Kaposi's sarcoma was seen in 0.5% of HIV-positive and 0% of HIV-negative women. Using multiple logistic regression models controlling for use of antiretrovirals and antifungals, in HIV-positive women the presence of oral candidiasis was associated with a CD4 count <200 cells/microl, cigarette smoking, and heroin/methadone use; the presence of hairy leukoplakia was not related to CD4 count but was associated with high viral load. Oral candidiasis and hairy leukoplakia are confirmed as being common features of HIV infection in women and appear to be associated with HIV viral load, immunosuppression, and various other behaviorally determined variables.

AIDS-Related Opportunistic Infections↗

PubMed1996

Will killing the last HIV1 particle cure AIDS patients? II: Second Part. Decrease of viral load and of T-suppressor cells, and increase of the cytotoxic cells, without effect on CD4, after the use of 10 virostatics applied in 3 or 4 drug combinations of different sequences. The time for CD4 immunotherapy?

We reported in the first part of this editorial and in an article AIDS therapy with five HIV1 virostatics applied in two then three, or initially three, or initially four agent combinations, given in 3 week sequences differing from each other due to drug rotation, the contrast between: a) the decrease of viral load, possible below the detectable level, b) the absence of effect on the helper CD4+, the CD8+ C57- cytotoxics and the CD8+ C57+ suppressor cells. We proposed a thesis according to which the HIV1-AIDS complex might have another pathogenic component other than HIV1, ie, a microchimerism graft-versus host reaction (GvH) or an autologous GvH-like reaction. Shifting from five to 10 virostatics owing to the availability of lamivudine or 3TC, stavudine or d4T and three HIV1 protease inhibitors, saquinavir, ritonavir and indinavir, applied according to the same modality, we have enhanced the reduction of viral load, and significantly decreased the CD8+ C57+ suppressor cell counts, and increased those of the CD8+ C57- cytotoxic cells. This result which indirectly shows the role of HIV1 in the increase of suppressor CD8+ cells, hence in the late loss of immune memory and of opportunistic infections, reinforces the thesis of a role, in AIDS pathogenesis, of a latent GvH reaction activated by HIV1 primo-infection, and its evolution from the hyperplastic phase to the hypoplastic one, which, inducing severe immune suppression, is responsible for HIV1 active infection relapse after the so-called latent phase. Hence the proposition we make, of an indication of CD4 modulation with non specific immunotherapy by bestatin, of which we showed the effect in another population of HIV1-AIDS complex patients. Its effect can be potentiated by tuftsin. When the suppressor cell number goes up over that of the cytotoxic one after the HIV1 active infection relapse, interferon gamma could be added, which, by amplifying the CD28 pathway on CD8+ cytotoxics, while suppressor cells lack CD28, which might reestablish a ratio of suppressor over cytotoxic cells nearer to normal. It remains that the role of the five secondarily included agents in the decrease of suppressor cells will only be attributed with certainty and entirely to their virostatic effect, if it is shown that none of them exerts a selective anti-suppressor cell action.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Durable hematologic complete response and suppression of HTLV-1 viral load following alemtuzumab in zidovudine/IFN-{alpha}-refractory adult T-cell leukemia.

Adult T-cell leukemia (ATL) is a highly chemoresistant and usually fatal T-cell malignancy due to the human T-cell lymphotropic virus-1 (HTLV-1). After chemotherapy failure, antiretrovirals and interferon-alpha (IFN-alpha) produce brief responses followed by progression and death. More effective agents and new approaches to detect and treat minimal residual disease are needed. ATL cells express CD52, the target of the antibody alemtuzumab, which is active in a preclinical model of ATL and is cytotoxic for p53-deficient cells. A patient with refractory chronic ATL in transformation achieved longer than a 1-year complete hematologic response following 12 weeks of outpatient subcutaneous alemtuzumab. Persistent suppression of HTLV-1 viral load, even at recovery of T cells, after alemtuzumab and efficient in vitro complement-mediated cytotoxicity of primary ATL cells with mutated TP53 were observed. The unprecedented response and the profound suppression of HTLV-1 viral load observed in this patient suggest that further clinical investigation of alemtuzumab in ATL is warranted.

Alemtuzumab↗

PubMed1998

Reduction of the viral load of HIV-1 after the intraperitoneal administration of dextrin 2-sulphate in patients with AIDS.

OBJECTIVE: To determine the safety and efficacy of the sulphated polysaccharide, dextrin 2-sulphate, when delivered to the lymphatic circulation by the peritoneal route. DESIGN: An open Phase I/II dose-escalation clinical study in which six patients with AIDS were treated with seven courses of dextrin 2-sulphate each lasting 1 month. METHODS: During each course of treatment, the drug was administered daily for 28 days using an intraperitoneal catheter. Viral load was measured at frequent intervals using a plasma tissue culture infectious dose (TCID) assay, a cellular TCID assay, p24 antigenaemia, HIV-1 RNA and HIV-1 DNA. Plasma beta-chemokine levels were also measured. RESULTS: Dose escalation was completed without toxicity. A total of 7 patient-months of treatment were completed. With increasing doses of dextrin 2-sulphate, the infectious plasma viraemia, cellular viraemia and p24 antigenaemia all fell during the period of drug administration, but with no significant change in HIV-1 RNA. This was associated with increased plasma levels of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. Dextrin 2-sulphate accumulated in peritoneal macrophages and induced the release of MIP-1alpha and MIP-1beta from these cells in vitro. These beta-chemokines could have augmented the cell surface-mediated anti-HIV-1 effect of dextrin 2-sulphate in vivo by binding to and blocking the CC-chemokine receptor-5. A second fall in infectious plasma viraemia, cellular viraemia, p24 antigenaemia and HIV-1 RNA was seen at day 100 which was then sustained for several months. A clinical improvement in Kaposi's sarcoma was also seen. CONCLUSIONS: Our results suggest that the intraperitoneal administration of dextrin 2-sulphate can reduce the replication of HIV-1 in patients with AIDS. With increasing doses of dextrin 2-sulphate, the fall in viral load was seen during the period of drug administration and again 2 months after completing treatment.

AIDS-Related Opportunistic Infections↗

PubMed2002

CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load.

The causal relationships among CD4 cell depletion, HIV replication, and immune activation are not well understood. HIV-2 infection, "nature's experiment" with inherently attenuated HIV disease, provides additional insights into this issue. We report the finding that in HIV-2 and HIV-1 patients with a comparable degree of CD4 depletion the imbalance in the relative sizes of the naive and memory T cell populations and the up-regulation of CD4 and CD8 cell activation markers (HLA-DR, CD38, CD69, Fas molecules) are similar, even though the viral load in the plasma of HIV-2-infected patients is two orders of magnitude lower than in HIV-1 patients and HIV-2 patients are known to have slower rates of CD4 T cell decline and a better clinical prognosis. Moreover, we found a similar increase in the frequency of cycling CD4 T cells (Ki67+), which was in strong correlation with the expression of activation markers. Finally, the level of T cell anergy, as assessed by the proliferative responses to CD3 stimulation and to a panel of microbial Ags, proved to be comparable in HIV-1 and HIV-2 patients with a similar degree of CD4 depletion despite large differences in viral load. Our data are consistent with a direct causal relationship between immune activation and CD4 cell depletion in HIV disease and an only indirect relation of these parameters to the virus replication rate. Invoking the concept of proximal immune activation and virus transmission, which links efficient transmission of virus to local cell activation and proliferation in response to Ags and inflammation, we propose an integrative interpretation of the data and suggest that strongly elevated immune activation induces CD4 cell depletion and not vice versa, with potential implications for the choice of treatment strategies.

Biomarkers↗

PubMed2002

Inclusion of Vpr accessory gene in a plasmid vaccine cocktail markedly reduces Nef vaccine effectiveness in vivo resulting in CD4 cell loss and increased viral loads in rhesus macaques.

We compared the immunogenicity of plasmid vaccines containing multiple human immunodeficiency virus (HIV) antigens and found that covaccination with plasmids expressing HIV-1 14 kDa vpr gene product profoundly reduces antigen-specific CD8-mediated cytotoxic T-cell activity (CTL). Interestingly, Th1 type responses against codelivered antigens (pGag-Pol, pNef, etc.) encoded by the plasmid vaccines were suppressed. This suggested that vpr might compromise CD8 T-cell immunity in vivo during infection. A pilot primate vaccine study was designed to test the hypothesis to compare the following groups: unvaccinated controls, animals vaccinated without simean immunodeficiency virus (SIV)-Nef antigen plasmid, and animals covaccinated with the identical plasmid antigen and a plasmid construct encoding SIV Vpr/Vpx. Animals were subsequently challenged intrarectally with pathogenic SIVmac251 after the final vaccination of a multiple immunization protocol. Control animals were all infected and exhibited high viral loads and rapid CD4+ T-cell loss. In contrast, the Nef plasmid-vaccinated animals were also infected but exhibited preservation of CD4+ T-cells and a multilog reduction in viral load compared with controls. Animals covaccinated multiple times with the Nef vaccine and pVpr/Vpx plasmid suffered rapid and profound loss of CD4+ T-cells. These results have important implications for the design of multicomponent and particle vaccines for HIV-1 as well as for our understanding of HIV/SIV pathogenesis in vivo.

Animals↗