Early prognostic indicators in primary perinatal human immunodeficiency virus type 1 infection: importance of viral RNA and the timing of transmission on long-term outcome

The time of perinatal human immunodeficiency virus type 1 (HIV-1) transmission and the pattern of early plasma viremia as predictors of disease progression were evaluated in infected infants followed from birth. Cox proportional hazards modeling demonstrated that a 1-log higher HIV-1 RNA copy number at birth was associated with a 40% increase in the relative hazard (RH) of developing CDC class A or B symptoms (P = .004), a 60% increase in developing AIDS (P = .01), and an 80% increase in the of risk death (P = .023) over the follow-up period of up to 8 years. The peak HIV-1 RNA copy number for infants during primary viremia was also predictive of progression to AIDS (RH, 9.9; 95% confidence interval [95% CI], 1.8-54.1; P = .008) and death (RH, 6.9; 95% CI, 1.1-43.8; P = .04). The results indicate that high levels of HIV-1 RNA at birth and during primary viremia are associated with early onset of symptoms and rapid disease progression to AIDS and death in perinatally infected children.     

Replication and tropism of human immunodeficiency virus type 1 as predictors of disease outcome in infants with vertically acquired infection

In a series of 97 infants born to mothers who were seropositive for human immunodeficiency virus type 1 (HIV-1), 18 were identified as infected within the first 60 days of life on the basis of viral culture and polymerase chain reaction findings. We studied viral burden in vivo by quantitative polymerase chain reaction and the in vitro replication pattern of the HIV-1 infecting strain by culturing patient cells with normal phytohemagglutinin-stimulated peripheral blood mononuclear cells. According to the lag phase before p24 antigen detection and the level of p24 production on peripheral blood mononuclear cells, HIV-1 isolates from these patients were classified as rapid/high (R/H), slow/high (S/H), and slow/low (S/L). The pattern of HIV-1 replication in vitro was significantly associated with the viral burden in vivo; the range of HIV-1 copies per 10(5) peripheral blood mononuclear cells was 10 to 38, 44 to 314, and 360 to 947 in children with isolates of the S/L, S/H, and R/H types, respectively. Viral tropism was assessed by culturing patient cells under end-point dilution conditions with either CD4+ T-lymphocytes or monocyte-derived macrophages. We found that children with S/L isolates harbored mainly monocytotropic variants; all infants with S/H or R/H isolates had T-lymphotropic variants and, in 7 of 11 cases, monocytotropic or amphitropic variants. All children with R/H isolates had HIV-related symptoms by the age of 4 months, and five had acquired immunodeficiency syndrome by the age of 1 year. At 1 year of age, four and no infants with S/H or S/L isolates, respectively, had HIV-1-related symptoms (p < 0.001), and none had acquired immunodeficiency syndrome (p = 0.006).     

Neurodevelopment, growth, and viral load in HIV-infected infants

The relation of HIV-1 infection to infant growth and neurodevelopment was studied prospectively in a cohort of 65 infants born to women at risk for HIV infection. No differences were observed at birth between infected infants (INF) and uninfected infants (SR) of HIV-infected women, and infants of uninfected women (SN) with similar socioeconomic background and exposure to drugs. However, postnatal linear growth and cognitive-motor development of INF infants were impaired when compared to SR and SN infants. Declines in linear growth were observed within the first 6 months of life, whereas delays in neurodevelopment were first appreciated at 12 months. In INF infants, decreased linear growth was positively correlated with developmental delay. Moreover, growth and development were both correlated with HIV viral load. INF infants with high plasma HIV RNA copies (> 5 x 10(5)/ ml) at 6 months of life were more likely to exhibit severe growth and developmental delay than infants with a lower viral burden. The implications of these findings with respect to the mechanism of action of HIV-related growth and neurodevelopmental impairments are discussed.     

RT-PCR comparative study of viral load levels in the HIV positive population in Puerto Rico before and after protease inhibitor regimen implanted

Ponce School of Medicine AIDS Research Program conducted a large scale viral load assessment of Puerto Ricans who are infected by human immunodeficiency virus type 1 (HIV-1) during the summer of 1996 through the Roche ACCESS program before general implementation of combination therapy. Since January 1997, it has monitored those HIV-1 patients who are under treatments at most HIV-1 health care clinics, including both public and private. The present study was conducted to evaluate how the new treatment has generally impacted on the HIV-1 disease status of HIV-1 infected population in the eight Immunology Clinics. Assessment was made by consecutively monitoring the changes in HIV-1 viral load profiles of the population from January to September, 1997. A large majority of samples were delivered for viral load assessment without information of their treatment status, and only a small number of samples were identifiable either as baseline or followup. Despite the paucity of individual information, remarkable improvements of HIV-1 (+) population at large were evident. For example, in the summer of 1996 (ACCESS), population median viral load was 51,842; only 9% of the population had viral load less than 500 viral RNA copies/ml plasma and 72% had over 10,000 copies/ml. By July-September, 1997, the population median dropped to 8,679 (83%); 23% were below 500 copies/ml (+156%) and the proportion of patients who had over 10,000 copies/ml was reduced to 48% (-33%). The group of individuals who were positively identified as "follow-up" (i.e., under active treatment) had a median of 37128 copies/ml (-94%); 28% were below 500 copies/ml (+211%) and only 40% had more than 10,000 copies/ml (-44%). It is obvious that the implementation of triple combination therapy by PASET in 1997, has very markedly improve the HIV-1 disease status of HIV-1 (+) population in Puerto Rico.     

Evaluation of human immunodeficiency virus (HIV) type 1 RNA levels in cerebrospinal fluid and viral resistance to zidovudine in children with HIV encephalopathy

The amount of human immunodeficiency virus (HIV) type 1 RNA and the presence of a codon 215 mutation indicative of zidovudine resistance were evaluated in cerebrospinal fluid (CSF) and plasma obtained from HIV-1-infected children. The level of HIV-1 RNA in CSF was highest in children with severe encephalopathy (n = 25; median, 430 copies/mL; range, 0-2.2 x 10(5) copies/mL) followed by the moderately encephalopathic (n = 7; median, 330; range, 0-1130) and nonencephalopathic groups (n = 9; median, 0; range, 0-566) (P = .007). There was no correlation between CSF and plasma HIV-1 RNA levels. Five of 7 children with the codon 215 mutation in CSF had a progression of encephalopathy, while all 8 children with wild type codon 215 had improved or stable disease during zidovudine treatment (P = .007). These findings suggest that increased viral replication and emergence of drug-resistant HIV-1 variants within the central nervous system may play a role in progression of HIV encephalopathy.     

Topical SDZ GLC-756, a novel dopamine D-1 antagonist and D-2 agonist, lowers intraocular pressure in conscious rabbits

OBJECTIVE: To investigate the longitudinal changes in serum HIV RNA, and to clarify whether the viral load early in infection has a predictive value for the clinical outcome; also, to correlate viral phenotype at seroconversion and changes in CD4 cell counts with viral burden. DESIGN: Twenty seroconverters with HIV isolates available at seroconversion had HIV RNA quantified by polymerase chain reaction (PCR) at seroconversion and thereafter every 6 months. Mean follow-up time was 65 months. Patients were classified according to viral phenotype at seroconversion, time to AIDS progression, serum viral load within the first year (less or more than 1.5 x 10(4) copies/ml). RESULTS: High viral load at seroconversion was followed by a significant decline within the first months (P < 0.0005). Decline to < 1.5 x 10(4) copies/ml was correlated with slower progression to AIDS (P < 0.05). A correlation between the rate of CD4 decline and the median viral load during the ensuing viral load plateau phase was also shown (P < 0.05). Subsequent to this phase the viral burden increased. Rapid progressors had higher viral load than slow- or non-progressors; this was particularly pronounced late in infection. Harbouring syncytium-inducing (SI) virus at seroconversion was associated with faster progression to AIDS than non-SI (NSI; P < 0.005). The increased in vitro replication rate of SI over NSI was not translated into significantly higher serum HIV RNA. CONCLUSION: Serum HIV RNA is high around the time of seroconversion. A significant decline within the first months hereafter is followed by a plateau phase, which in turn is followed by an increase in HIV RNA. HIV RNA early in infection has a predictive value for the clinical outcome. The increased virulence of SI over NSI virus did not translate into significantly higher HIV RNA values.     

Dysregulation of membrane-bound tumor necrosis factor-alpha and tumor necrosis factor receptors on mononuclear cells in human immunodeficiency virus type 1 infection: low percentage of p75-tumor necrosis factor receptor positive cells in patients with advanced disease and high viral load

The correlation of persistent tumor necrosis factor-alpha (TNF-alpha) activation with disease progression in patients infected with human immunodeficiency virus type 1 (HIV-1), suggests a role for TNF-alpha in the pathogenesis of HIV-1 infection. In the present study, we examined by flow cytometry the expression of membrane-bound (m) components of the TNF system in 33 HIV-1-infected patients and 12 healthy controls. While peripheral blood mononuclear cells (PBMC) from asymptomatic and symptomatic non-acquired immune deficiency syndrome (AIDS) patients showed a significantly increased percentage of mTNF-alpha+ and mTNF receptor (TNFR)+ cells compared with controls, this was not found in the AIDS group. Compared with healthy controls, AIDS patients had a significantly decreased percentage of both monocytes and lymphocytes expressing p75-TNFR. PBMC from AIDS patients showed a higher p75-TNFR mRNA level and a higher spontaneous release of soluble p75-TNFR than healthy individuals, suggesting enhanced cell surface turnover of this TNFR. The low expression of TNFRs on both lymphocytes and monocytes in the AIDS group was associated with high numbers of HIV-1 RNA copies in plasma, low numbers of CD4+ lymphocytes, and high serum levels of soluble TNFRs. AIDS patients had a decreased percentage of CD8+ lymphocytes expressing TNFRs compared with healthy controls. In contrast, these patients, as well as symptomatic non-AIDS patients, had an increased percentage of TNF-alpha+ and TNFRs+ cells among remaining CD4+ lymphocytes. The pattern of abnormalities seen in AIDS patients suggests a role for persistent activation of the TNF system in the accelerated CD4+ lymphocyte destruction, the enhanced HIV-1 replication, and the markedly impaired antimicrobial defense in advanced HIV-1-related disease.     

Virus burden in lymph nodes and blood of subjects with primary human immunodeficiency virus type 1 infection on bitherapy

At present, it is not known whether undetectable plasma viremia corresponds to an absence of human immunodeficiency virus type 1 (HIV-1) replication in lymphoid tissues. This issue has been explored in 11 subjects with primary HIV-1 infection treated with zidovudine plus didanosine by evaluating virologic markers in blood and lymphoid tissues 9-18 months after initiation of treatment. These markers include plasma viremia, measured with a sensitive assay with a detection limit of 20 HIV-1 RNA copies/mL, infectious virus titers and proviral DNA in lymph node mononuclear cells, and HIV-1 RNA in lymphoid tissue. Five subjects had plasma viremia <20 copies/mL and showed no evidence of viral replication in lymphoid tissue. Six subjects had both detectable plasma viremia and evidence of HIV-1 RNA in lymphoid tissue. The results indicate that absence of detectable HIV RNA in lymphoid tissue is associated with viremia levels of HIV-1 RNA <20 copies/mL.     

Local cerebral blood flow, local cerebral glucose utilization, and flow-metabolism coupling during sevoflurane versus isoflurane anesthesia in rats

Antepartum plasma hepatitis C virus (HCV) RNA was quantified in 155 mothers coinfected with HCV and human immunodeficiency virus type 1 (HIV-1), and HCV RNA was serially assessed in their infants. Of 155 singleton infants born to HCV antibody-positive mothers, 13 (8.4%) were HCV infected. The risk of HCV infection was 3.2-fold greater in HIV-1-infected infants compared with HIV-1-uninfected infants (17.1% of 41 vs. 5.4% of 112, P = .04). The median concentration of plasma HCV RNA was higher among the 13 mothers with HCV-infected infants (2.0 x 10(6) copies/mL) than among the 142 mothers with HCV-negative infants (3.5 x 10(5) copies/mL; P < .001), and there were no instances of HCV transmission from 40 mothers with HCV RNA concentrations of < 10(5) copies/mL. Women dually infected with HIV-1 and HCV but with little or no detectable HCV RNA should be reassured that the risk of perinatal transmission of HCV is exceedingly low.     

Virulence of human immunodeficiency virus

Virulence is relative capacity of a virus, compared to other closely related viruses, to produce disease in a host. Viral strains considered as virulent have been described in HIV-1 infected patients. They are characterized in vitro by enhanced cellular host range, rapid kinetic of replication and increased capacity of syncytium induction. Some genetic modification of the V3 loop in the envelope gene have been associated with the emergence of these strains. But at AIDS diagnosis, and even at the terminal stage of AIDS, only about half of the patients harbour syncytium inducing variants. There are much evidence for continuous viral replication throughout all stages of HIV-1 infection. There is no viral latency state in the natural HIV infection. This increasing viral burden might have a pivotal role in the pathogenesis of HIV disease. HIV-2 is less pathogenic than HIV-1. The nature of the viral determinants responsible for this reduced virulence remains unknown. In the simian immunodeficiency virus model, virulent and avirulent strains have been described and the nef gene seems to have a critical role in pathogenicity.     

Delayed maturation of Hering-Breuer inflation reflex activity in preterm infants

We have previously shown that the strength of the Hering-Breuer inflation reflex (HBIR) diminishes between 2 and 12 mo of age in full-term babies. The purpose of this study was to determine whether the onset of this decline had commenced by 3 to 4 mo of age in healthy full-term infants and whether preterm delivery influences the pattern of maturation. Serial measurements of HBIR activity using the end-inspiratory occlusion technique were made in 25 preterm and 27 full-term infants at matched postnatal and postconceptional ages during the first 6 mo of life. Although similar levels of reflex activity were observed at birth (mean +/- SD of 101.2% +/- 42.4% in preterm, and 101.0% +/- 33.9% in full-term infants), by 40 wk postconceptional age (PCA) (i.e., term equivalent) HBIR activity (mean +/- SD) had increased to 121.7% +/- 51.2% in preterm infants, which was significantly greater than that in full-term infants of similar PCA (95% CI of difference: 0.2; 41.2%). By 15 wk postnatal age (PNA), HBIR activity had decreased to 68.8% +/- 26.6% in full-term infants, but remained significantly higher in those delivered prematurely (87.8% +/- 32.7%). However, when measurements were repeated at approximately 4 mo after the expected rather than actual date of delivery, these differences were no longer evident (95% CI difference preterm-full-term: -21.2; 3.8%). This study suggests that important transitions in respiratory control mechanisms occur between 8 and 15 wk PNA in full-term infants and that these changes are delayed in preterm infants.     

In vitro characterization of adult primary human immunodeficiency virus type 1: demonstration of distinctive single-cell killing phenotypes in spite of similar levels of viral replication

Two primary human immunodeficiency virus (HIV)-1 biologic clones have been studied extensively in a system using CD4 T cell-enriched peripheral blood lymphocytes and anti-CD4 antibody to measure viral replication kinetics and single-cell cytopathicity. Biologic clones from a person with AIDS replicated to high levels and were cytopathic in the absence of syncytium formation. Unexpectedly, biologic clones from an adult long-term nonprogressor were noncytopathic in spite of similar levels of viral replication. A correlation has recently been demonstrated between reduced mitochondrial viability and cell death in HIV-1-infected cultures. Peripheral blood-derived CD4 T cells infected with the cytopathic clone showed a progressive reduction in mitochondrial viability, while those infected with the noncytopathic clone demonstrated functionally viable mitochondria. These studies demonstrate that primary HIV-1-induced cytopathicity is separable from syncytium formation and replication rate.     

Cytotoxic T lymphocytes generation capacity in early life with particular reference to HIV

Most of our knowledge concerning the presence of virus specific cytotoxic T lymphocytes (CTL) in early life has been provided by studies of CTL activities against human immunodeficiency virus type 1 (HIV-1) in infected infants born to HIV-infected mothers. HIV-specific cytolytic responses were found to be similar in perinatally infected children compared with adults, with respect to the nature of effector cells, protein recognized and the ability to control viral replication. CTL responses measured immediately after PBMC isolation (ex vivo activated CTL) were observed predominantly in children with no or mild symptoms, and the presence of in vitro activated CTL was found to be associated with the absence of severe symptoms during the first year of life and survival over 5 years.     

Quantitation of human immunodeficiency virus type 2 DNA in peripheral blood mononuclear cells by using a quantitative-competitive PCR assay

A new quantitative-competitive PCR-based human immunodeficiency virus type 2 (HIV-2) proviral DNA assay (QC-PCR) was developed and used to determine the proviral load in HIV-2-infected individuals. Proviral load varied considerably, with means of 1,831 copies per 10(6) peripheral blood mononuclear cells for asymptomatic subjects (n = 19) and 2,587 for AIDS patients (n = 2). HIV-2 viral and proviral loads also varied significantly over time in asymptomatic patients. These data suggest that a high level of virus replication occurs throughout the asymptomatic phase of HIV-2 infection.     

Development of AIDS in a chimpanzee infected with human immunodeficiency virus type 1

The condition of a chimpanzee (C499) infected with three different isolates of human immunodeficiency virus type 1 (HIV-1) for over 10 years progressed to AIDS. Disease development in this animal was characterized by (i) a decline in CD4+ cells over the last 3 years; (ii) an increase in viral loads in plasma; (iii) the presence of a virus, termed HIV-1JC, which is cytopathic for chimpanzee peripheral blood mononuclear cells; and (iv) the presence of an opportunistic infection and blood dyscrasias. Genetic analysis of the V1-V2 region of the envelope gene of HIV-1JC showed that the virus present in C499 was significantly divergent from all inoculating viruses (> or = 16% divergent at the amino acid level) and was suggestive of a large quasispecies. Blood from C499 transfused into an uninfected chimpanzee (C455) induced a rapid and sustained CD4+-cell decline in the latter animal, concomitant with high plasma viral loads. These results show that HIV-1 can induce AIDS in chimpanzees and suggest that long-term passage of HIV-1 in chimpanzees can result in the development of a more pathogenic virus.     

Oral immunization of macaques with attenuated vaccine virus induces protection against vaginally transmitted AIDS

The chimeric simian-human immunodeficiency virus SHIVKU-1, bearing the envelope of human immunodeficiency virus type 1 (HIV-1), causes fulminant infection with subtotal loss of CD4(+) T cells followed by development of AIDS in intravaginally inoculated macaques and thus provides a highly relevant model of sexually transmitted disease caused by HIV-1 in human beings. Previous studies using this SHIV model had shown that the vpu and nef genes were important in pathogenesis of the infection, and so we deleted portions of these genes to create two vaccines, DeltavpuDeltanefSHIV-4 (vaccine 1) and DeltavpuSHIVPPc (vaccine 2). Six adult macaques were immunized subcutaneously with vaccine 1, and six were immunized orally with vaccine 2. Both viruses caused infection in all inoculated animals, but whereas vaccine 1 virus caused only a nonproductive type of infection, vaccine 2 virus replicated productively but transiently for a 6- to 10-week period. Both groups were challenged 6 to 7 months later with pathogenic SHIVKU-1 by the intravaginal route. All four unvaccinated controls developed low CD4(+) T-cell counts (<200/microliter) and AIDS. The 12 vaccinated animals all became infected with SHIVKU-1, and two in group 1 developed a persistent productive infection followed by development of AIDS in one. The other 10 have maintained almost complete control over virus replication even though spliced viral RNA was detected in lymph nodes. This suppression of virus replication correlated with robust antiviral cell-mediated immune responses. This is the first demonstration of protection against virulent SHIV administered by the intravaginal route. This study supports the concept that sexually transmitted HIV disease can be prevented by parenteral or oral immunization.     

Circular forms of unintegrated human immunodeficiency virus type 1 DNA and high levels of viral protein expression: association with dementia and multinucleated giant cells in the brains of patients with AIDS

Thirty-one histologically abnormal brains from patients with AIDS were studied in order to establish the relationship between multinucleated giant cells, viral protein expression, the various forms of human immunodeficiency virus type 1 (HIV-1) DNA, and clinical evidence of dementia. Unintegrated HIV-1 DNA of 2 to 8 kb was found in 22 of the 31 brains. Multinucleated giant cells without any other pathology were found in 14 cases; unintegrated 1-long terminal repeat (1-LTR) circular forms of HIV-1 DNA and strongly positive immunohistochemistry for gp41 and p24 were found in most of these brains. Most of these patients had a clinical diagnosis of HIV-1-associated dementia and cerebral atrophy. In all the other brains studied, 1-LTR circles were absent and immunohistochemistry for gp41 and p24 was usually negative. Very few of these patients had a clinical diagnosis of dementia. Sequence comparison of the LTR region from integrated HIV-1 DNA with that from unintegrated 1-LTR circular forms of HIV-1 DNA in 12 cases showed no significant differences. A further comparison of these brain-derived LTR sequences with LTR sequences derived directly from lymphoid tissue also showed strong sequence conservation. The V3 loop of the virus from the brain was sequenced in 6 cases and had a non-syncytium inducing-macrophage-tropic genotype. Our results show that (i) although unintegrated HIV-1 DNA was present in most brains from patients with AIDS, molecular evidence of high levels of viral replication was associated with the presence of multinucleated giant cells and dementia, and that (ii) the HIV-1 LTR is not a determinant of neurotropism. These observations suggest that replication of HIV-1 and not just the presence of HIV-1 DNA within giant cells makes the important contribution to central nervous system damage.     

A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study

CONTEXT: Current guidelines recommend that individuals infected with the human immunodeficiency virus type 1 (HIV-1) be treated using combinations of antiretroviral agents to achieve sustained suppression of viral replication as measured by the plasma HIV-1 RNA assay, in the hopes of achieving prolonged remission of the disease. However, until recently, many drug combinations have not led to sustained suppression of HIV-1 RNA. OBJECTIVE: To compare the virologic effects of various combinations of nevirapine, didanosine, and zidovudine. DESIGN: Double-blind, controlled, randomized trial. SETTING: University-affiliated ambulatory research clinics in Italy, the Netherlands, Canada and Australia (INCAS). PATIENTS: Antiretroviral therapy-naive adults free of the acquired immunodeficiency syndrome with CD4 cell counts between 0.20 and 0.60x10(9)/L (200-600/microL). INTERVENTION: Patients received zidovudine plus nevirapine (plus didanosine placebo), zidovudine plus didanosine (plus nevirapine placebo), or zidovudine plus didanosine plus nevirapine. MAIN OUTCOME MEASURE: Plasma HIV-1 RNA. RESULTS: Of the 153 enrolled patients, 151 were evaluable. At week 8, plasma HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.05). The proportions of patients with plasma HIV-1 RNA levels below 20 copies per milliliter at week 52 were 51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.001). Viral amplification was attempted in 59 patients at 6 months. Viral isolation was unsuccessful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively. Among patients from whom virus could be amplified, resistance to nevirapine was found in all 11 patients receiving zidovudine plus nevirapine and in all 5 patients receiving triple drug therapy. Rates of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51) for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple drug therapy groups, respectively (P=.08). CONCLUSIONS: Triple drug therapy with zidovudine, didanosine, and nevirapine led to a substantially greater and sustained decrease in plasma viral load than the 2-drug regimens studied. Our results also suggest that suppression of viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of quantitation of the most sensitive test available, may at least forestall the development of resistance.     

Patterns of viral replication correlate with outcome in simian immunodeficiency virus (SIV)-infected macaques: effect of prior immunization with a trivalent SIV vaccine in modified vaccinia virus Ankara

The dynamics of plasma viremia were explored in a group of 12 simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) that had received prior immunization with either nonrecombinant or trivalent (gag-pol, env) SIV-recombinant vaccinia viruses. Three distinct patterns of viral replication observed during and following primary viremia accounted for significant differences in survival times. High-level primary plasma viremia with subsequently increasing viremia was associated with rapid progression to AIDS (n = 2). A high-level primary plasma virus load with a transient decline and subsequent progressive increase in viremia in the post-acute phase of infection was associated with progression to AIDS within a year (n = 6). Low levels of primary plasma viremia followed by sustained restriction of virus replication were associated with maintenance of normal lymphocyte subsets and intact lymphoid architecture (n = 4), reminiscent of the profile observed in human immunodeficiency virus type 1-infected long-term nonprogressors. Three of four macaques that showed this pattern had been immunized with an SIV recombinant derived from the attenuated vaccinia virus, modified vaccinia virus Ankara. These data link the dynamics and extent of virus replication to disease course and suggest that sustained suppression of virus promotes long-term, asymptomatic survival of SIV-infected macaques. These findings also suggest that vaccine modulation of host immunity may have profound beneficial effects on the subsequent disease course, even if sterilizing immunity is not achieved.