Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients

OBJECTIVES: To assess the effect of early syphilis on HIV viral load (VL) and CD4 cell count in patients with HIV and to analyze factors associated with changes in HIV VL and CD4 cell count. DESIGN: Multicenter study of a series of patients with HIV who were diagnosed with early syphilis infection during 2004 through 2005. Patients who started or changed their highly active antiretroviral therapy (HAART) regimen during the analysis period were excluded. RESULTS: One hundred eighteen patients were analyzed: 95.8% were men, mean patient age was 38.2 years, 83.9% were homosexual men, 50.8% were on antiretroviral therapy at the time syphilis was diagnosed, and HIV and syphilis diagnoses were coincident in 38 (32.2%) cases. CD4 cell counts were lower during syphilis than before (590 vs. 496 cells/microL; P = 0.0001) and after syphilis treatment (509 vs. 597 cells/microL; P = 0.0001). The HIV VL increased in 27.6% of patients during syphilis. The only factor associated with an HIV VL increase was not being on HAART, and the only factor associated with a CD4 count decrease >100 cells/microL during syphilis was the prior CD4 cell count. CONCLUSIONS: Syphilis infection was associated with a decrease in the CD4 cell count and an increase in the HIV VL in almost one third of the patients. In this series, more than two thirds of the syphilis cases were diagnosed in patients who were previously known to be infected with HIV.     

Dissociation of CD4(+) cell counts from viral load and association with immune complexes in HIV(+) hemophilia patients

OBJECTIVE: We have postulated that the host autoimmune response regulates and mediates CD4 depletion during HIV infection by opsonization of circulating CD4(+) lymphocytes carrying autoreactive immune complexes (IC) consisting of complement-fixing IgM and IgG, and during advanced stages of HIV disease of IgM/ IgG/gp120 complexes. In this retrospective study, we investigated whether HIV causes CD4 depletion by direct cytotoxicity or indirectly by induction of a host autoimmune response. PATIENTS AND METHODS: In 1996, 12 HIV(+) hemophilia patients were converted to highly active antiretroviral therapy (HAART), while 10 other patients were maintained on conventional antiretroviral treatment and another 11 patients refused to be treated with antiretroviral drugs. The host immune response of these 33 HIV(+) patients was studied during the periods of minimum viral replication (Interval 1), subsequent rise in viral replication with strong replication dynamic (Interval 2), and maximum viral replication (Interval 3). The patients were categorized into three groups according to viral load (VL). Group A: patients with low level VL (n=10) showed a modest increase from <80 to <4 log 10 HIV-1 RNA copies per milliliter plasma during the observation period; Group B: patients with medium level VL (n=12) showed a stronger increase from <80 to >4 log 10 copies per milliliter plasma; and Group C: patients with high level VL (n=11) consistently had a median of >4 log 10 copies per milliliter plasma, during Intervals 1-3, with the exception of one patient who during Interval 2 had 4800 copies per milliliter. Blood lymphocyte subpopulations, proportions of CD4(+) blood lymphocytes coated with IgM, IgG, C3d and/or gp120, in vitro responses to mitogens and pooled allogeneic stimulator cells, as well as numbers of HIV-1 RNA copies per milliliter plasma were measured. RESULTS: Sequential analysis of VL, IC load on CD4(+) blood lymphocytes and CD4 counts showed that an increasing VL was not associated with CD4 depletion, when the proportion of IC-coated circulating CD4(+) blood lymphocytes remained stable. When, CD4 counts and IC load were analyzed during corresponding intervals of retroviral replication in the three patient groups, a higher VL was associated with lower CD4 counts only when the IC load (IgG or gp120/IgG) on CD4(+) lymphocytes was higher as well. CONCLUSION: These data suggest that HIV regulates and mediates CD4 depletion in part by the induction of autoreactive ICs against CD4(+) lymphocytes, especially complement-fixing autoreactive IgG and gp120/IgG complexes.     

CD4+ CD25+调节性T细胞在HIV/AIDS患者中的作用及其与HIV病毒载量的相关性研究

目的 研究HIV感染者／AIDS患者外周血CD4^＋ CD25^＋ 调节性T细胞（CD4^＋ CD25^＋ regulatory Tcell，Treg）频率、功能及其临床意义。方法 选择31例HIV感染者／AIDS患者和30例健康对照者，采用流式细胞仪检测各组外周血Treg的表型和频率。采取MACS磁珠分选CD4^＋CD25^＋T细胞，利用[^3H]胸腺嘧啶掺入法检测CD4^＋ CD25^＋T细胞在特异性HIV抗原刺激下对CD4^＋ CD25-T细胞的增殖影响。结果HIV／AIDS患者组与正常对照组相比较，外周血CD4^＋ CD25^＋ T细胞频率在统计学上差异无统计学意义。与正常对照组比较，HIV感染者外周血CD4^＋ CD25^＋ T细胞频率升高，差异有统计学意义（P〈0.01）；与正常对照组比较，AIDS患者者外周血CD4^＋ CD25^＋ T细胞频率降低，差异有统计学意义（P〈0．0001）。HIV RNA病毒载量与患者外周血CD4^＋ CD25^＋ T细胞数量呈正相关性（P〈0．01）。CD4^＋ CD25^＋ T细胞具有抑制HIV特异性的CD4^＋ CD25^- T细胞的增殖作用。结论HIV感染者／AIDS患者的细胞免疫功能紊乱，CD4^＋ CD25^＋ T细胞能抑制HIV感染者／AIDS患者的HIV特异性细胞免疫反应，促进HIV病毒复制，与形成持续HIV感染有关。     

Immune activation correlates better than HIV plasma viral load with CD4 T-cell decline during HIV infection

This study addressed the role of T-cell immune activation in determining HIV-1 plasma viral load and CD4+ T-cell blood levels during HIV-1 infection. A decrease of blood CD4 levels and CD4/CD8 ratios and an increase of CD8 levels in both treated (n = 35) and untreated (n = 19) HIV-positive individuals were more strongly correlated to immune activation (log percentage of HLA-DR+CD3+ cells; R = -0.78, R = -0.77, and R = 0.58, respectively; p <.0001) than to CD4 T-cell proliferation (log percentage of Ki-67+CD4+ cells; R = -0.57 [p <.0001], R = -0.48 [p <.001], and R = 0.37 [p <.01], respectively) or to viral load (R = -0.36 [p <.01], R = -0.23 [p =.09], R = 0.13 [p =.35], respectively). Because almost half of the Ki-67+CD4+ cells were also positive for CTLA-4 (a marker for activated nonproliferating cells), the correlation of CD4 levels to Ki-67 expression is only partially related to cell proliferation and more likely represents mainly immune activation of the cells without proliferation. Taken together, these results suggest that immune activation is the major determinant of CD4 decline and should therefore be considered central for the monitoring of HIV infection and its outcome after antiviral treatment.     

Influence of peak viral load on the extent of CD4+ T-cell depletion in simian HIV infection

Simian HIV (SHIV) infection of macaques with CXCR4 tropic viruses results in early and profound CD4 T-cell depletion in the first few weeks of infection. Analyzing data from a large study of vaccination and SHIV-89.6P challenge, we observe a strong correlation between peak viral load and the extent of CD4 T-cell depletion in acute infection, consistent with a simple kinetic model of viral infection of CD4 T cells. We have modeled the dynamics of the interaction of virus and CD4 T cells over time to investigate the rate of CD4 T-cell infection and death. This analysis indicates that up to 80% of CD4 T cells are infected at peak viremia and that the proportion of CD4 T cells destroyed is correlated with the peak viral load. The simple relation between viral load and CD4 T-cell depletion allows prediction of the level of viral control required to prevent CD4 T-cell depletion in acute SHIV infection. Whether such a simple relation also holds for HIV or simian immunodeficiency virus infections remains to be determined, particularly in the gut and other anatomic sites in which most early T-cell depletion occurs.     

Association of immune complexes and plasma viral load with CD4+ cell depletion, CD8+ DR+ and CD16+ cell counts in HIV+ hemophilia patients. Implications for the immunopathogenesis of HIV-induced CD4+ lymphocyte depletion

OBJECTIVE: There is evidence that HIV induces CD4+ depletion in part by the formation of immune complexes (IC) that attach to CD4+ blood lymphocytes. In the present study we examined the relationship of IC-coated CD4+ blood cells with retroviral replication in HAART-treated patients. PATIENTS And METHODS: 52 hemophilia patients were studied from 1997 to 1999. Lymphocyte subsets, IgM, IgG and gp120 on CD4+ blood cells, in vitro responses of lymphocytes to mitogens, plasma neopterin and plasma viral load were measured. RESULTS: Patients with detectable viral replication and without ICs on CD4+ blood lymphocytes had a lower viral load (4100 versus 21000 HIV-1 mRNA copies/ml; P = 0.079) and higher CD4+ cell counts (310/microl versus 161/microl; P = 0.035) than patients with ICs on circulating CD4+ lymphocytes. Among patients with < 80 HIV-1 mRNA copies/ml, IC- individuals had slightly higher CD4+ lymphocyte counts than IC+ patients (384/microl versus 316/microl; n.s.). Further evidence for the clinical relevance of the ICs was obtained when 18 patients who had an undetectable viral load at previous investigations were analyzed. Among patients with a stable undetectable viral load, CD4+ counts increased in 6 of 8 IC- but in none of 2 IC+ individuals. In patients whose viral load increased during the observation period, 5 of 6 IC- but none of 2 IC+ individuals showed higher CD4+ cell counts. Impaired virus killing is suggested by lower CD16+ (35/microl versus 107/microl; P = 0.016), higher CD3+ DR+ (178/microl versus 66/microl; P = 0.006), and higher CD8+ DR+ (142/microl versus 34/microl; P = 0.017) cell counts in IC(-) patients compared to IC- patients without detectable viral load. Strong retroviral replication induced strong T cell dysfunctions. Fewer CD3+ 25+ blood lymphocytes (19/microl versus 47/microl; P = 0.006) and a lower in vitro response of T lymphocytes to the mitogens Con A (RR: 0.3 versus 1.2; P=0.023) and CD3 mab (RR: 0.5 versus 2.4; P = 0.012) was observed in IC+ patients with detectable versus undetectable viral load. CONCLUSION: Our data suggest that ICs on circulating CD4+ blood lymphocytes are primarily associated with CD4+ lymphocyte depletion whereas the plasma viral load is primarily associated with decreased T lymphocyte activation, lower CD16+ counts, and higher CD8+ DR+ lymphocytes which might be the effector cells for virus elimination.     

CD4 T cell responses to influenza infection

Immune responses to viral infections involve a complex orchestration between innate signals and adaptive responses of specific T and B cells. Anti-viral CD4 cells can direct CD8 responses by secreting a Type 1 panel of cytokines including IFN-gamma, IL-2 and TNF-alpha and can drive B cell production of IgG2a to neutralize infective viral particles. This review will focus specifically on the role of CD4 cells in the immune response to influenza, an acute, localized respiratory viral infection. We suggest that CD4 cells act as direct effectors in protection against influenza, may contribute to immunopathology and generate functionally distinct memory subsets.     

Assessment of the association between HIV viral load and CD4 cell count on the occurrence of oropharyngeal candidiasis in HIV-infected patients

BACKGROUND: Oropharyngeal candidiasis (OPC) is the most frequently observed oral infection in HIV-infected individuals. Historically, lower CD4 counts have been associated with an increased prevalence of OPC in HIV-infected patients, but HIV viral load has also recently been recognized as a possible predictive factor. OBJECTIVE: We examined the impact of viral load and blood CD4 cell count on the occurrence of OPC using modern exploratory statistical analyses. METHODS: The exploratory and inferential methods of classification and regression trees (CARTs) and logistic regression were used to compare the impact of viral load and CD4 cell counts on OPC status in 161 HIV-infected individuals from an outpatient clinic population in New Orleans. RESULTS: The use of stepwise logistic regression and CART to classify individual OPC status both identified viral load as the most important covariate, followed by CD4 cells counts. Age, sex, and highly active antiretroviral therapy use were also found to be associated with OPC status. CONCLUSIONS: These data strongly suggest that low viral load distinguishes those not at risk for OPC with high viral load, which also includes a heterogeneous set of predictors for OPC status, has the highest impact on OPC classification.     

Survival in children with perinatal HIV infection and very low CD4 lymphocyte counts

OBJECTIVES: To evaluate clinical conditions associated with mortality in HIV-infected children with CD4+ counts <100 cells/microl. METHODS: The Pediatric Spectrum of HIV Disease Project is a longitudinal medical record review study with eight study sites in the United States, which have been enrolling children since 1989. Survival time from baseline very low CD4 count (<100 cells/microl) to death was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to evaluate the effect of clinical variables on mortality. RESULTS: Of 522 children (>/=1 year of age) with serial CD4+ T-lymphocyte measurements, the median age at the first very low CD4 count was 4.8 years. The estimated median survival following the first very low CD4 count was 36 months. The following factors present at the first very low CD4 count were independently associated with a higher risk of death: younger age, weight-for-age >2 standard deviations below the mean, and previously diagnosed AIDS. The subsequent development of cytomegalovirus (CMV)-associated disease, Mycobacterium avium intracellulare (MAI) infection, wasting syndrome, or esophageal candidiasis was also independently associated with a higher risk of death. CONCLUSION: Survival in HIV-infected children with very low CD4 counts before introduction of highly active antiretroviral therapy was highly variable. Poor nutritional status and the development of CMV disease or MAI infection were associated with the shortest survival times.     

HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome

Early immunological events during acute HIV infection are thought to fundamentally influence long-term disease outcome. Whereas the contribution of HIV-specific CD8 T cell responses to early viral control is well established, the role of HIV-specific CD4 T cell responses in the control of viral replication after acute infection is unknown. A growing body of evidence suggests that CD4 T cells-besides their helper function-have the capacity to directly recognize and kill virally infected cells. In a longitudinal study of a cohort of individuals acutely infected with HIV, we observed that subjects able to spontaneously control HIV replication in the absence of antiretroviral therapy showed a significant expansion of HIV-specific CD4 T cell responses-but not CD8 T cell responses-compared to subjects who progressed to a high viral set point (P = 0.038). Markedly, this expansion occurred before differences in viral load or CD4 T cell count and was characterized by robust cytolytic activity and expression of a distinct profile of perforin and granzymes at the earliest time point. Kaplan-Meier analysis revealed that the emergence of granzyme A(+) HIV-specific CD4 T cell responses at baseline was highly predictive of slower disease progression and clinical outcome (average days to CD4 T cell count <350/μl was 575 versus 306, P = 0.001). These data demonstrate that HIV-specific CD4 T cell responses can be used during the earliest phase of HIV infection as an immunological predictor of subsequent viral set point and disease outcome. Moreover, these data suggest that expansion of granzyme A(+) HIV-specific cytolytic CD4 T cell responses early during acute HIV infection contributes substantially to the control of viral replication.     

Relation between CD4 cell counts and HIV RNA levels at onset of opportunistic infections

OBJECTIVE: To evaluate the relation between CD4 and HIV RNA levels at the onset of specific opportunistic infections (OIs) in HIV-infected patients. DESIGN AND METHODS: The OIs occurring between June 1996 and December 1998 were retrospectively reviewed, considering only the episodes of major and minor OIs in patients with simultaneously available CD4 and plasma HIV RNA determinations before clinical onset who had been untreated or on stable antiretroviral therapy (ART) for at least 2 months. RESULTS: Two hundred seventy-four episodes of different OIs were considered in 216 patients; the median CD4 count was 35 cells/mm3 (range: 0-1154 cells/mm(3)), and the median HIV RNA count was 5.1 log cp/mL (range: < 1.9-6.7 log copies/ml). The different HIV RNA levels were significantly associated with different OIs regardless of CD4 and ART (p < .0001), even when only those occurring in patients with a CD4 count of < or = 50 cells/mm(3) were considered (p = .0049). Kaposi sarcoma, esophageal candidiasis, oropharyngeal candidiasis, and Mycobacterium avium complex disease were associated with significantly above-average median HIV RNA levels, and varicella-zoster virus infection was associated with below-average levels. CONCLUSIONS: Different OIs are associated at their onset with significantly different HIV RNA levels, regardless of CD4 cell counts and ART.     

Neutralization profiles of sera from human immunodeficiency virus (HIV)-infected individuals: relationship to HIV viral load and CD4 cell count

The relationship of the neutralizing activity (NA) profile of sera from human immunodeficiency virus (HIV)-infected individuals to the HIV viral load and the absolute CD4 count was examined. The NA of 24 serum samples against autologous isolates (AI) and HIV type 1 strain MN was examined. Three NA patterns were recognized. Nine sera neutralized both AI and MN (+/+), six sera neutralized MN but not AI (-/+), and nine sera failed to neutralize both AI and MN (-/-). The identification of the three neutralization patterns (+/+, -/+, and -/-) indicated that resistance to neutralization was progressive. A reciprocal relationship between the viral burden of the patients and the NA profiles was observed. The nine subjects with a -/- NA profile had a plasma viral load of > or =5 x 10(4) copies/ml and a cellular viral burden of > or =1,122 infectious units per million viable cells, which were significantly different from those of the other groups (P < 0.02). These patterns were independent of the phenotypic characteristics of the virus. Longitudinally, subjects with a -/- profile at baseline gained their HIV-specific NA by 24 weeks of antiretroviral therapy when this was associated with a >/=1-log(10) decline in the plasma HIV viral load. The sera from week 24 from some patients were able to neutralize both the 24-week and the baseline dominant virus isolates. A change in CD4 cell count of 50 or more in either direction predicted a -/- or +/+ profile. The verification of the autologous NA profile might be important in selecting patients who may benefit from immune-based therapies involving neutralizing monoclonal antibodies.     

HCV RNA viral load is independent from CD4 cell count and plasma HIV RNA viral load in immunocompetent HIV-HCV co-infected patients: a 3-years follow-up study

Background

HCV RNA viral load is an important predictor of sustained virological response and, recently, a significant correlation with liver fibrosis was described. We investigated on possible influence of clinical and viro-immunological variables on HCV viral load in HIV-HCV co-infected patients over a study time of three years (2009-2012).

Methods

We retrospectively enrolled 98 adult patients with a diagnosis of chronic HIV infection in 2009, a diagnosis of chronic HCV infection with a detectable plasma HCV RNA in 2009 and 2012, HCV therapy-naïve or with failed and stopped antiviral treatment before June 2008. The following variables were recorded: age, gender, HCV genotype, IL28B rs12979860 CC genotype, HCV treatment status, advanced liver fibrosis diagnosis, antiretroviral therapy, CD4+ cell count, HCV viral load, HIV RNA (plasma HIV-1 RNA levels were measured from blood samples every three months at least). The correlation was established using linear regression analysis, analysis of variance and Fisher’s exact test. Comparisons between groups were performed using Fisher’s exact test, the independent samples t-test and the t-test for paired data, as appropriate, for continuous variables. A mixed mode (ME) maximum likelihood linear regression model was constructed to evaluate the dependence of HCV viral load.

Results

HCV RNA levels did not change significantly from 2009 to 2012 (from 3924650?±?5320177 IU/ml to 3085128?±?3372347 IU/ml, p?=?0.13); the CD4+ count increased significantly (from a mean of 576 to a mean of 654, p?=?0.003). Using linear regression, a positive correlation was observed for HCV load and genotype 1 (p?=?0.002), nonresponder status (p?=?0.04) and with interleukin 28B CC allele (p?=?0.05). Other studied covariates failed to reach a significant correlation.

Conclusions

The HCV RNA load, a known pretreatment predictor of response to antiviral therapy, was independent of the two main parameters of HIV disease, plasma HIV RNA and CD4 cell count, over an observation time of 3 years in patients with recovered or spontaneously maintained immunocompetence.

     

Relationship of HIV viral loads,CD4 counts,and HAART use to health-related quality of life

OBJECTIVE: To understand the relationship of viral load (VL), CD4 counts, and highly active antiretroviral therapy (HAART) use to health-related quality of life (HRQL). DESIGN: Cross-sectional analysis of 513 HIV-infected patients. Primary outcomes were four domains of HRQL: physical functioning (PF), role function (RF), energy levels (EL), and health perceptions (HP). The authors examined univariate and multivariate relationships between VL, CD4, and HAART use to each HRQL domain, after adjustment for potential confounders. RESULTS: In univariate analyses, compared with patients with CD4 > 500, those with CD4 < 200 (p =.001) or 200 to 500 (p =.002) had lower PF and RF scores, and patients with undetectable VL had higher PF scores than patients with VL log10 2.6 to 4.0 (p =.02) and > log10 4.0 (p =.01). In multivariate analyses, compared with patients with CD4 > 500, patients with CD4 < 200 had lower PF (-8.8 points; p <.01), RF (-9.3 points; p <.01), and HP (-7.8 points; p <.001). Patients with log10 VL 2.6 to 4.0 had lower PF scores (-7.7 points; p <.01) versus undetectable VL. After adjusting for VL and CD4 counts, HAART use was associated with lower PF scores (-5.4 points; p <.05). CONCLUSIONS: Efforts to improve patients' CD4 counts are likely to also improve HRQL. Lowering viral loads may improve physical functioning, but only if VL are suppressed to undetectable levels. In this analysis, HAART had negative effects on PF that were independent of its effects on CD4 and VL. For adherent patients, these adverse effects of HAART on PF are likely to be outweighed by the positive effects that HAART exerts through lowering VL and increasing CD4 counts.     

Maternal viral load,CD4 cell count and vertical transmission of HIV-1

HIV load and CD4 cell numbers were measured among 95 HIV infected women during pregnancy in order to determine their value as prognostic markers for transmission of virus from mother to infant. Among the 94 live births, 13 children were infected with HIV, 69 were uninfected and 12 were of unknown infection status. HIV RNA levels, as measured by nucleic acid sequence based amplification, were significantly higher (P < 0.001) in women who transmitted virus than among those who did not transmit and maternal viral load was a stronger predictor of transmission than CD4 cell number. The predicted rate of transmission relative to maternal HIV RNA was 2% at 1,000 copies, 11% at 10,000 copies and 40% at 100,000 copies/ml. Little variation in viral load occurred during pregnancy and there was an association between viral load and prematurity, the mean gestation at delivery decreasing by 1.3 weeks for every 10-fold increase in maternal HIV RNA (P = 0.007). This study demonstrates that a high level of maternal HIV RNA is a risk factor for transmission of virus to the infant and maternal viral load is of more value as a prognostic marker for transmission risk than CD4 cell number. High viral load is also associated with premature delivery. Maternal viral load is therefore a useful marker on which to base management decisions during pregnancy. J. Med. Virol. 54:113–117, 1998. © 1998 Wiley-Liss,Inc.     

The relation between symptoms, viral load, and viral load set point in primary HIV infection

OBJECTIVES: To examine the relation between symptoms, initial viral load, and viral load set point in primary HIV infection (PHI). DESIGN: Prospective cohort of patients with preseroconversion or recent seroconversion HIV infection (typically <60 days) in San Francisco. METHODS: Subjects were questioned about 21 potential PHI symptoms at enrollment and were subsequently followed with viral load measures. RESULTS: The analysis included 57 subjects with preseroconversion HIV infection and 120 with recent seroconversion. In univariate analysis, most symptoms and the total number of symptoms were each associated with a significantly higher initial viral load. In stepwise multiple linear regression, however, only the number of symptoms was independently associated with a higher initial viral load, with an increase in the initial viral load of 0.08 log10 per additional symptom (P < 0.001). In univariate analysis, more PHI symptoms were associated with a higher viral load set point, but in a multivariable mixed-effects model, this association was accounted for by the initial viral load, which was strongly correlated with viral load set point (R = 0.44, P < 0.001). CONCLUSIONS: A high initial viral load was associated with more symptoms during PHI. The strong correlation between initial HIV-1 RNA viral load levels and viral load set point suggests that early interactions between the HIV-1 virus and a new host, even before fully developed adaptive immune responses, are important in establishing viral load set point.     

Influence of CD4+ T cell counts on viral evolution in HIV-infected individuals undergoing suppressive HAART

We analyzed the viral C2-V4 envelope diversity, glycosylation patterns, and dS/dN ratios of plasma HIV-1 in an attempt to better understand the complex interaction between viral quasispecies and the host-selective pressures pre- and post-HAART. Phylogenetic analysis of the envelope gene of five patients revealed monophyletic clustering in patients with higher CD4+ T cell counts and sequence intermingling in those with lower CD4+ T cells in relation to the stage of HAART. Our analyses also showed clear shifts in N-linked glycosylation patterns in patients with higher CD4+ T cells, suggesting possible distinct immunological pressures pre- and post-HAART. The relative preponderance of synonymous/nonsynonymous changes in the envelope region suggested a positive selection in patients with higher CD4+ T cells, whereas lack of evidence for positive selection was found in the patients with lower CD4+ T cells. An exception to the last analysis occurred in the only patient who reached complete viral suppression, maybe due to drug pressure exerted over the pol gene that may obscure the immune pressure/selection at the envelope in this analysis. All these indications may suggest that even when HAART generates viral suppression, quasispecies evolve in the envelope gene probably resulting from host-selective pressure.     

CD4 T cell recovery is slower in patients experiencing viral load rebounds during HAART.

To determine whether viral load rebounds during HAART impact on CD4+ T cell recovery and immune reconstitution, we studied a prospective cohort of 355 antiretroviral naive patients enrolled to be randomized in a trial of three strategies of induction/maintenance HAART. The extent of immune reconstitution in blood through 72 weeks of antiretroviral treatment was evaluated. Lymphocyte subset markers (CD4, CD8, CD45RA, CD62L, CD16, CD19), activation markers (HLA-DR, CD38, CD25) were performed by cytometry analysis. Our results showed that plasma HIV-1 RNA was suppressed to below 500 copies per ml through week 72 in 240 patients (group 1) while the remaining 115 patients experienced at least one viral rebound (group 2). At baseline, CD4 cell count was higher and HIV-1 RNA was lower in group 1 than in group 2. Over 72 weeks, mean increase in CD4+ T cell count was 0.32 cell/mm3/day in group 1 and only 0.14 cell/mm3/day in group 2 (P < 0.0001). However, the patterns of changes in CD4+ and CD8+ T cell subsets during therapy were very similar across the two groups with only subtle and very limited differences. We conclude that permanent control of HIV replication could be necessary for faster immune reconstitution.