 |
 |
|
Home |
Current Issue |
Past Issues |
In the Clinic |
ACP Journal Club |
CME |
Collections |
Audio/Video |
Mobile |
Subscribe |
Tools |
Help |
ACP Online
|
15 April 1995 | Volume 122 Issue 8 | Pages 573-579
Objective: To investigate the relation between the quantity of human immunodeficiency virus type 1 (HIV-1) RNA in plasma and the risk for the acquired immunodeficiency syndrome (AIDS) or a decline in the CD4+ T-cell count after seroconversion.
Design: Prospective study.
Patients: 62 homosexual men with documented HIV-1 seroconversion.
Setting: University outpatient setting.
Measurements: Clinical status, CD4+ T-cell counts, and plasma and serum samples were obtained every 6 months. Human immunodeficiency virus RNA in plasma was quantitated with a branched-DNA (bDNA) assay. Serum samples were assayed for neopterin, ß2-µglobulin, and immune complex dissociated HIV-1 p24 antigen.
Results: 18 of 62 (29%) men developed AIDS; 21 (34%) had a significant decline in the CD4+ T-cell count without AIDS; and 23 [37%] had a stable CD4+ T-cell count. For each participant, HIV-1 RNA results were categorized into one of four groups: 1) detection of HIV-1 RNA (>1 x 104 genome equivalents/mL [Eq/mL]) in all samples; 2) detection in most samples [
Conclusions: Plasma HIV-1 RNA is a strong, CD4+ T-cell-independent predictor of a rapid progression to AIDS after HIV-1 seroconversion.
Several new methods have been developed to directly measure HIV-1 nucleic acid in body fluids. One of these technologies is the branched-DNA (bDNA) signal amplification method for quantitating HIV-1 RNA in plasma [14]. Although less sensitive than RNA detection by the polymerase chain reaction (PCR), the bDNA method has the advantage of large sample capacity, speed, reproducibility, and a format similar to an enzyme-linked immunosorbent assay.
The ability of the bDNA assay or other HIV-1 RNA detection methods to predict clinical outcome in HIV-1 infection has not been clearly defined in appropriate cohorts or been compared with the ability of other predictive markers. Previous studies have shown a strong correlation between disease stage and the amount of circulating HIV-1, whether measured as cell-free infectious virus [15, 16], viral proteins [11, 12], or RNA [17, 18]. Recent studies have shown that an increase in HIV-1 expression in peripheral blood mononuclear cells can precede immunologic deterioration by 1 to 2 years [17, 18]. Our objective, therefore, was to compare plasma HIV-1 RNA with determinations of serum p24 antigen, neopterin, and ß2-µglobulin levels and CD4+ T-cell counts as predictors of outcome in a cohort of homosexual men with documented HIV-1 seroconversion.
The initial pilot study population consisted of 10 seroprevalent men (unknown date of seroconversion) enrolled in the Pittsburgh portion of the Multicenter AIDS Cohort Study (MACS). Five of these men developed AIDS (Centers for Disease Control and Prevention [CDC] 1987 definition) after 35 to 74 months of follow-up (median, 59 months), and five remained asymptomatic with stable CD4+ T-cell counts after a similar follow-up interval (median, 56 months). The second study population consisted of 62 homosexual men enrolled in the MACS who had documented seroconversion (change from negativity for HIV-1 antibody to positivity). Eighteen of these men progressed to AIDS (CDC 1987 definition) by a median of 3.8 years after seroconversion (maximum, 6.5 years), and 44 did not develop AIDS after a median follow-up of 5.4 years (maximum, 8.3 years). Details about the recruitment and characteristics of the MACS cohort have been described previously [19]. All participants gave written informed consent, and the MACS protocol was approved by the Internal Review Board of the University of Pittsburgh.
Study Samples
The study samples were selected from stored ( –70°C) longitudinal plasma and serum samples obtained from enrollees at 6-month intervals as part of the MACS protocol. In patients who developed AIDS, the samples tested were obtained from the seroconversion visit (first visit at which the patient was positive for the HIV-1 antibody), the most recent visit before AIDS diagnosis, and equally spaced visits in between. In patients without AIDS, the samples tested were obtained from the seroconversion visit; visits 1, 2, and 3 years after seroconversion; and the last available visit, which occurred as long as 8.3 years after seroconversion.
Definition of Outcomes
Study patients were classified into one of three outcome groups: 1) AIDS; 2) decline in the CD4 count; and 3) stable CD4 count. Patients in the AIDS outcome group (n = 18) met the CDC 1987 case definition for AIDS. For each patient who had seroconversion and did not develop AIDS, we used linear regression to fit a line through prospective CD4+ T-cell measurements (minimum of three measurements per patient). We calculated the slope of each line and determined the statistical significance of the negative slopes. Patients with declining CD4 counts (n = 21) had statistically significant (P < 0.05) negative slopes but did not develop AIDS during follow-up. Patients with stable CD4 counts (n = 23) had no significant decline in the CD4+ T-cell count during follow-up, and 6 of 23 patients (26.1%) had a positive slope, that is, an increasing linear trend in the number of CD4+ T cells.
Measurement of T-Lymphocyte Subsets
We measured T-lymphocyte subsets in whole blood by staining them with fluorescent dye-conjugated monoclonal antibodies specific for CD3, CD4, and CD8 (Becton Dickinson, Mountain View, California) as previously described [20]. The total number of CD4+ T cells was determined by multiplying the percentage of lymphocytes that were CD4+ T cells by the total lymphocyte count.
Serum ß2-Microglobulin and Neopterin Assays
We measured serum ß2-µglobulin (Kabi Pharmacia, Uppsala, Sweden) and serum neopterin levels (Henning, Berlin, Germany) with commercial radioimmunoassays and standards provided by the manufacturers. Four replicates of normal control serum were included in each assay to assess variability. The coefficient of variation for control samples was 15% or less.
Serum Immune Complex Dissociated p24 Assay
Immune complex dissociated (ICD) p24 antigen levels were measured with a commercial enzyme immunoassay (Dupont, NEN Products, Wilmington, Delaware). The ICD p24 antigen levels in serum were interpolated from a standard curve provided by the manufacturer. The assay has a sensitivity of 12 pg of p24 antigen/mL. The interassay coefficient of variation for the p24 standards was less than 10%.
Plasma and Cellular HIV-1 RNA Assays
Levels of HIV-1 RNA in plasma samples were quantitated with the Quantiplex HIV-1 RNA assay, which is based on bDNA signal amplification technology (Chiron Corp., Emeryville, California). This assay measures HIV-1 RNA associated with viral particles that are pelleted from 1.0-mL plasma samples (23 500 g for 1 hour at 4 °C). The assay has a quantitation limit of 1 x 104 HIV-1 genome equivalents per mL of plasma (Eq/mL) and is linear at levels as high as 1.6 x 106 Eq/mL. For this study, the interassay coefficient of variation for the positive control samples run with each assay was 11.2%. Additional details about the assay procedure and its performance characteristics have been described previously [14].
We categorized longitudinal plasma HIV-1 RNA results from individual patients into one of four groups: 1) detection of HIV-1 RNA (>1 x 104 Eq/mL) in all samples tested [n = 9]; 2) detection in most (
Assays for neopterin, ß2-µglobulin, ICD p24, and HIV-1 RNA were done in duplicate on coded serum or plasma samples. Samples from a given patient were batch-tested to minimize the potential effect of interassay variability.
Semi-quantitative PCR-based assays for cellular HIV-1 gag RNA were done on stored peripheral blood mononuclear cell samples as described previously [17].
Statistical Analyses
The pilot study data are shown in the tables and figures to familiarize the reader with the raw data obtained from the bDNA assay. All cellular PCR results were adjusted per million CD4+ T cells. Analyses of the data set from patients with HIV-1 seroconversion were similarly stratified by outcome group. The Fisher exact test, chi-square test, and Wilcoxon rank-sum test were done where noted in the text. We estimated the association between progression to AIDS and laboratory covariates at seroconversion by multiple logistic regression analysis using BMDP statistical software (BMDP Statistical Software, Inc., Los Angeles, California).
An initial pilot study of plasma HIV-1 RNA quantitation was done in 10 seroprevalent men enrolled in the MACS. Five of the men developed AIDS after 35 to 64 months of follow-up (progressors), and 5 remained asymptomatic with stable CD4+ T-cell counts (nonprogressors) after 38 to 74 months of follow-up. The median duration of follow-up for progressors and nonprogressors was similar (59 and 56 months, respectively). The bDNA assay was done on stored longitudinal plasma samples from 4 to 6 time points for each patient. Figure 1 shows the plasma HIV-1 RNA levels in the nonprogressors and progressors. Levels of HIV-1 RNA in all five nonprogressors were less than the limit of quantitation (<1 x 104 Eq/mL) at each time point during the 38 to 74 months of follow-up (Figure 1). In contrast, HIV-1 RNA levels in the progressors were greater than 1 x 104 Eq/mL at the initial time point (3 of 5 patients) or increased to greater than 1 x 104 Eq/mL (2 of 5 patients) before AIDS developed. Plasma HIV-1 RNA levels increased 30 to 50 months before the diagnosis of AIDS, suggesting that plasma HIV-1 RNA could be an early predictor of AIDS (Figure 1). ARTICLE
Quantitation of HIV-1 RNA in Plasma Predicts Outcome after Seroconversion
50%]; 3) detection in fewer than 50% of samples; and 4) detection in none of the samples. Detection of HIV-1 RNA in all or most samples was strongly associated with AIDS (16 of 18 patients) and a decline in the CD4+ T-cell count (13 of 21 patients) compared with a stable CD4+ T-cell count (4 of 23 patients; P < 0.001). Conversely, the absence of HIV-1 RNA (<1 x 104 Eq/mL) in all or most samples was associated with stable CD4+ T-cell counts (19 of 23 patients) and a lower risk for AIDS or decline in the CD4+ T-cell count (10 of 39 patients; P < 0.001). In multivariate analysis of all laboratory values at the seroconversion visit, a plasma HIV-1 RNA level greater than 1 x 105 Eq/mL was the most powerful predictor of AIDS (odds ratio, 10.8; P = 0.01).
The course of infection with human immunodeficiency virus type 1 (HIV-1) varies considerably. Although the median interval between HIV-1 infection and the development of the acquired immunodeficiency syndrome (AIDS) in adults is 10 to 11 years [1], some infected persons rapidly progress to AIDS in less than 5 years [2]. Still others remain asymptomatic without evidence of immunologic decline for more than 6 years [3]. The biological basis of this variability is unknown, but differences in viral strains, host immune responses [4], and exposure to microbial [5] or environmental cofactors probably contribute. The variable course of HIV-1 infection causes uncertainty for the infected person and complicates the design and interpretation of therapeutic trials because of unrecognized differences in prognosis. Many clinical and laboratory markers have been used to estimate prognosis in patients with HIV-1 infection [6]. Markers of AIDS development include HIV-related symptoms [7, 8], depletion of CD4+ T cells [9], cutaneous anergy [7, 10], elevated serum ß2-µglobulin and neopterin levels [9], HIV-1 p24 (core) antigenemia [11, 12], and syncytium-inducing HIV-1 phenotype [13]. None of these markers is ideal; all have limitations in sensitivity, specificity, or predictive power. The single best predictor of AIDS onset identified thus far is the percentage or absolute number of circulating CD4+ T cells [9], but less variable and earlier markers of risk for AIDS are needed.
Methods
Top
Methods
Results
Discussion
Author & Article Info
References
Study Populations 50%) samples [n = 24; mean percentage of positive samples, 67.3%]; 3) detection in fewer than 50% of samples [n = 16; mean percentage of positive samples, 29.3%]; and 4) detection in none of the samples tested (n = 13). We identified an additional subgroup (n = 6) that showed evidence for clearance of detectable HIV-1 RNA from plasma, that is, two or more consecutive negative samples and no further positive samples after one or two initial positive samples.
Results
Top
Methods
Results
Discussion
Author & Article Info
References
HIV-1 Quantitation by Branched DNA and Polymerase Chain Reaction in Seroprevalent Patients
|
We compared the results of the bDNA assay with those of a semi-quantitative PCR assay of HIV-1 gag RNA in stored peripheral blood mononuclear cell samples obtained at the same times as the plasma samples (Table 1). Despite the differences in sample types and quantitative methods, the levels of HIV-1 RNA in plasma and peripheral blood mononuclear cells were strongly correlated (Spearman rank-order correlation coefficient, 0.66; P < 0.001). Cellular HIV-1 gag RNA levels remained low throughout follow-up in nonprogressors but increased in progressors as AIDS developed.
|
Study of HIV-1 Seroconversion
The findings of the pilot study led to a larger evaluation of plasma HIV-1 RNA quantitation in 62 men with known dates of HIV-1 seroconversion. Eighteen of the men (29%) progressed to AIDS after a median of 3.8 years (maximum, 6.5 years). Twenty-one patients (34%) had a significant decline in the CD4+ T-cell count but did not develop AIDS (CD4-decline group), and 23 (37%) had stable CD4+ T-cell counts without symptoms (stable-CD4 group). The median duration of follow-up for the CD4-decline and stable-CD4 groups were similar (5.3 and 5.5 years, respectively). We compared the ability of plasma HIV-1 RNA with that of serum neopterin, ß2-µglobulin, and ICD p24 antigen to discriminate between the outcome groups.
Serum Neopterin and ß2-Microglobulin
The median longitudinal neopterin and ß2-µglobulin levels in the three outcome groups are shown in (Figure 2). Overall, the median neopterin and ß2-µglobulin levels in the outcome groups did not change significantly over time. Median neopterin levels for the AIDS group, the CD4-decline group, and the stable-CD4 group ranged from 17.8 to 21.0 nmol/L, 11.9 to 18.0 nmol/L, and 9.3 to 14.0 nmol/L, respectively. Corresponding values for ß2-µglobulin levels were 3.0 to 3.6 µg/L, 2.1 to 3.5 µg/L, and 2.0 to 2.5 µg/L, respectively. Neopterin and ß2-µglobulin levels were significantly higher in the AIDS group than in the other groups (P < 0.05; Wilcoxon test). However, neopterin or ß2-µglobulin levels in the CD4-decline group and the stable-CD4 group did not significantly differ at any time point after seroconversion. In fact, the overall median neopterin and ß2-µglobulin levels for the stable-CD4 group were higher than those for the CD4-decline group (13.7 nmol/L compared with 11.9 nmol/L and 2.5 µg/L compared with 2.3 µg/L, respectively).
|
Serum Immune Complex Dissociated p24 Antigen and Plasma HIV-1 RNA Levels in Patients with HIV-1 Seroconversion
In Figure 3, the proportion of samples for each outcome group that had detectable serum ICD p24 antigen (>12 pg/mL) is shown as a function of time after seroconversion. In the first year after seroconversion, 36.3% of samples in the AIDS group were positive for p24 antigen compared with 4% to 9% of the samples in the other groups (P < 0.001; Fisher exact test). The proportion of samples for the AIDS group that were positive for p24 antigen increased to 66.7% by the fifth year after seroconversion. In the first 4 years after seroconversion, 0% to 22.7% of samples in the stable-CD4 and CD4-decline groups were positive for p24 antigen. No significant differences in p24 antigen positivity were noted between the stable-CD4 and CD4-decline groups in this interval (Fisher exact test).
|
Risk for AIDS Development
Table 2 shows the proportion of men developing AIDS as a function of HIV-1 RNA positivity, stratified by the CD4+ T-cell count at seroconversion. In patients with no detectable HIV-1 RNA in plasma for the first 2 years after seroconversion, the proportion developing AIDS was 6% or less. In contrast, when more than one plasma sample was positive for HIV-1 RNA within the first 2 years of seroconversion, the proportion of patients developing AIDS ranged from 45% to 86%, depending on whether the initial CD4+ T-cell count was less than 500/mm3 (86%) or 500/mm3 or more (45%). In addition, the mean plasma HIV-1 RNA level at the seroconversion visit was significantly higher in patients who developed AIDS than in those who did not (74.1 x 103 Eq/mL compared with 18.9 x 103 Eq/mL; P < 0.001; Wilcoxon test).
|
We did a logistic regression analysis to determine the strength and independence of the laboratory variables as predictors of AIDS development. All laboratory measurements from the seroconversion visit, including CD4+ T-cell counts and levels of HIV-1 RNA, ICD p24 antigen, neopterin, and ß2-µglobulin, were eligible for entry into the model. In this analysis, the quantity of HIV-1 RNA in plasma was categorized into three strata: greater than 1 x 105 Eq/mL; 1 x 104 to 105 Eq/mL; or less than 1 x 104 Eq/mL.
Plasma HIV-1 RNA was the first and only variable that was entered into the stepwise model; no other marker significantly improved the model fit when forced in after HIV-1 RNA. A plasma HIV-1 RNA level greater than 1 x 105 Eq/mL at the seroconversion visit was associated with an odds ratio for AIDS development of 10.8 (P = 0.01).
Discussion
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
These findings provide strong additional evidence that the course of HIV-1 infection parallels that of HIV-1 viremia. Failure of host immune mechanisms to adequately suppress viremia during the earliest stages of infection appears to be a critical factor in rapid progression to AIDS. Clearance of HIV-1 RNA to levels less than 1 x 104 Eq/mL after seroconversion indicates a better prognosis because this was observed only in persons who did not develop AIDS during follow-up.
These finding are in agreement with those in the recent report by Jurriaans and colleagues [21] that serum HIV-1 RNA levels 3 years after seroconversion, measured by a quantitative nucleic acid sequence-based amplification technique, were significantly lower in persons who did not progress to AIDS within 5 years than in those who did. However, Jurriaans and colleagues [21] did not observe a significant difference in serum HIV-1 RNA levels at seroconversion between progressors and nonprogressors. This discordance with our observation may be related to differences between the two studies in the interval after seroconversion at which initial samples were obtained, as well as differences in the type of sample tested (serum compared with plasma), the method of HIV-1 RNA quantitation (quantitative nucleic acid sequence-based amplification technique compared with bDNA), and the patient cohort studied.
Serum ICD p24 antigenemia was also associated with AIDS development, but only in univariate analyses. Immune complex dissociated p24 antigenemia was a less sensitive marker than plasma HIV-1 RNA; only 36% of samples from persons developing AIDS had detectable serum ICD p24 antigen within the first year of infection compared with 73% for HIV-1 RNA. In addition, ICD p24 antigen could not discriminate persons at risk for a significant decline in the CD4+ T-cell count from those in whom CD4+ T-cell counts remained stable.
Serum ß2-µglobulin and neopterin levels were significantly elevated in the AIDS group within the first year of seroconversion. This is consistent with findings in previous reports that ß2-µglobulin and neopterin are associated with AIDS development [9]. The differences in median values between the outcome groups were small, however, and did not increase with time. Most important, neither marker could discriminate the CD4-decline group from the stable-CD4 group. Median ß2-µglobulin and neopterin levels were actually higher in the stable CD4 group than in the CD4-decline group.
In the initial pilot study of seroprevalent men, we compared the bDNA assay with a semi-quantitative PCR assay of cellular HIV-1 gag RNA. Both assays gave similar findings (Table 1). When plasma HIV-1 RNA levels were below the detection limit of the bDNA assay, fewer than 100 copies of HIV-1 gag RNA per million CD4+ T cells were detected by PCR (mean, 19.9 copies/106 CD4+ T cells). Similarly, when plasma HIV-1 RNA was detectable by bDNA, much higher levels of cellular HIV-1 RNA were detected by PCR (mean, 2813 copies/106 CD4 cells). Increases in HIV-1 RNA occurring before clinical disease progression were also reflected in both assays. Thus, in this study, the plasma level of HIV-1 RNA correlated with intracellular expression of HIV-1 gag RNA in circulating lymphocytes (Spearman r = 0.66; P < 0.001).
Although PCR-based detection methods have greater sensitivity than bDNA technology for detection of HIV-1 RNA, the bDNA assay can be done in standard clinical laboratories without the need for special facilities or procedures to avoid carry-over contamination of amplification reactions with PCR product. In addition, the assay is reproducible (interassay coefficient of variation, 11.2%) and rapid; 42 samples can be tested in duplicate in only 36 hours. These characteristics make the bDNA assay a suitable candidate for use in clinical practice.
In summary, the quantity of HIV-1 RNA in plasma was a strong, CD4+ T-cell-independent predictor of a rapid progression to AIDS after HIV-1 seroconversion in homosexual men. Measurement of plasma HIV-1 RNA may substantially improve prognostic accuracy in HIV-1 infection, which would be advantageous for clinical management of infected persons.
Author and Article Information
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
References
|
|---|
|
TopMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
1. Munoz A, Wang MC, Bass S, Taylor JM, Kingsley LA, Chmiel JS, et al. Acquired immunodeficiency syndrome (AIDS)-free time after human immunodeficiency virus type 1 (HIV-1) seroconversion in homosexual men. Multicenter AIDS Cohort Study Group. Am J Epidemiol. 1989; 130:530-9.
2. Phair J, Jacobson L, Detels R, Rinaldo C, Saah A, Schrager L, et al. Acquired immune deficiency syndrome occurring within 5 years of infection with human immunodeficiency virus type 1: the Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1992; 5:490-6.
3. Sheppard HW, Lang W, Ascher MS, Vittinghoff E, Winkelstein W. The characteristics of non-progressors: long term HIV-1 infection with stable CD4+ T-cell levels. AIDS. 1993; 7:1159-66.
4. Kaslow RA, Duquesnoy R, VanRaden M, Kingsley L, Marrari M, Friedman H, et al. A1, Cw7, B8, DR3 HLA antigen combination associated with rapid decline of T-helper lymphocytes in HIV-1 infection. A report from the Multicenter AIDS Cohort Study. Lancet. 1990; 335:927-30.
5. Webster A, Lee CA, Cook DG, Grundy JE, Emery VC, Kernoff PB, et al. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet. 1989; 2:63-6.
6. Tsoukas CM, Bernard NF. Markers predicting progression of human immunodeficiency virus-related disease. Clin Microbiol Rev. 1994; 7:14-28.
7. Redfield RR, Wright DC, Tramont EC. The Walter Reed staging classification for HTLV-III/LAV infection. N Engl J Med. 1986; 314:131-2.
8. Phair J, Munoz A, Detels R, Kaslow R, Rinaldo C, Saah A. The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N Engl J Med. 1990; 332:161-5.
9. Fahey JL, Taylor JM, Detels R, Hofmann B, Melmed R, Nishanian P, et al. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med. 1990; 322:166-72.
10. Blatt SP, Hendrix CW, Butzin CA, Freeman TM, Ward WW, Hensley RE, et al. Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients. Ann Intern Med. 1993; 119:177-84.
11. Allain JP, Laurian Y, Paul DA, Verroust F, Leuther M, Gazengal C, et al. Long-term evaluation of HIV antigen and antibodies to p24 and gp41 in patients with hemophilia. Potential clinical importance. N Engl J Med. 1987; 317:1114-21.
12. de Wolf, Goudsmit J, Paul DA, Lange JM, Hooijkaas C, Schellekens P, et al. Risk of AIDS related complex and AIDS in homosexual men with persistent HIV antigenaemia. Br Med J. 1987; 295:569-72.
13. Koot M, Keet IP, Vos AH, de Goede RE, Roos MT, Coutinho RA, et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med. 1993; 118:681-8.
14. Pachl C, Todd JA, Kern DG, Sheridan J, Fong SJ, Stempien M, et al. Rapid and precise quantitation of HIV-1 RNA in plasma using a branched DNA (bDNA) signal amplification assay. J Aquir Immun Defic Syndr. 1995; (In press).
15. Ho DD, Moudgil T, Alam M. Quantitation of human immunodeficiency virus in the blood of infected persons. N Engl J Med. 1989; 321:1621-5.
16. Coombs RW, Collier AC, Allain JP, Nikora B, Leuther M, Gjerset GF, et al. Plasma viremia in human immunodeficiency virus infection. N Engl J Med. 1989; 321:1626-31.
17. Gupta P, Kingsley L, Armstrong J, Ding M, Cottrill M, Rinaldo C. Enhanced expression of human immunodeficiency type 1 correlates with development of AIDS. Virology. 1993; 196:586-95.
18. Saksela K, Stevens C, Rubinstein P, Baltimore D. Human immunodeficiency virus type 1 mRNA expression in peripheral blood cells predicts disease progression independently of the numbers of CD4+ lymphocytes. Proc Natl Acad Sci U S A. 1994; 91:1104-8.
19. Kaslow RA, Ostrow DG, Detels R, Phair JP, Polk BF, Rinaldo CR. The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristic of the participants. Am J Epidemiol. 1987; 126:310-8.
20. Giorgi JV, Cheng HL, Margolick JB, Bauer KD, Ferbas J, Waxdal M, et al. Quality control in the flow cytometric measurement of T-lymphocyte subsets: the Multicenter AIDS cohort study experience. The Multicenter AIDS Cohort Study Group. Clin Immunol Immunopathol. 1990; 55:173-86.
21. Jurriaans S, Van Gemen B, Weverling GJ, Van Strijp D, Nara P, Coutinho R, et al. The natural history of HIV-1 infection: virus load and virus phenotype independent determinants of clinical course? Virology. 1994; 204:223-33.
This article has been cited by other articles:
|
|
 |
|
  G. D. Sanders, A. M. Bayoumi, M. Holodniy, and D. K. Owens Cost-Effectiveness of HIV Screening in Patients Older than 55 Years of Age Ann Intern Med, June 17, 2008; 148(12): 889 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Pusterla, S. Mapes, and W. D. Wilson Use of viral loads in blood and nasopharyngeal secretions for the diagnosis of EHV-1 infection in field cases Vet Rec., May 31, 2008; 162(22): 728 - 729. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Monceaux, L. Viollet, F. Petit, M. C. Cumont, G. R. Kaufmann, A. M. Aubertin, B. Hurtrel, G. Silvestri, and J. Estaquier CD4+ CCR5+ T-Cell Dynamics during Simian Immunodeficiency Virus Infection of Chinese Rhesus Macaques J. Virol., December 15, 2007; 81(24): 13865 - 13875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Milush, K. Stefano-Cole, K. Schmidt, A. Durudas, I. Pandrea, and D. L. Sodora Mucosal Innate Immune Response Associated with a Timely Humoral Immune Response and Slower Disease Progression after Oral Transmission of Simian Immunodeficiency Virus to Rhesus Macaques J. Virol., June 15, 2007; 81(12): 6175 - 6186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Miller, M. Genesca, K. Abel, D. Montefiori, D. Forthal, K. Bost, J. Li, D. Favre, and J. M. McCune Antiviral Antibodies Are Necessary for Control of Simian Immunodeficiency Virus Replication J. Virol., May 15, 2007; 81(10): 5024 - 5035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Ayele, R. Schuurman, T. Messele, W. Dorigo-Zetsma, Y. Mengistu, J. Goudsmit, W. A. Paxton, M. P. de Baar, and G. Pollakis Use of Dried Spots of Whole Blood, Plasma, and Mother's Milk Collected on Filter Paper for Measurement of Human Immunodeficiency Virus Type 1 Burden J. Clin. Microbiol., March 1, 2007; 45(3): 891 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Viollet, V. Monceaux, F. Petit, R. H. T. Fang, M.-C. Cumont, B. Hurtrel, and J. Estaquier Death of CD4+ T Cells from Lymph Nodes during Primary SIVmac251 Infection Predicts the Rate of AIDS Progression J. Immunol., November 15, 2006; 177(10): 6685 - 6694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Miyake, K. Ibuki, Y. Enose, H. Suzuki, R. Horiuchi, M. Motohara, N. Saito, T. Nakasone, M. Honda, T. Watanabe, et al. Rapid dissemination of a pathogenic simian/human immunodeficiency virus to systemic organs and active replication in lymphoid tissues following intrarectal infection. J. Gen. Virol., May 1, 2006; 87(Pt 5): 1311 - 1320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Mori, C. Sugimoto, S. Ohgimoto, E. E. Nakayama, T. Shioda, S. Kusagawa, Y. Takebe, M. Kano, T. Matano, T. Yuasa, et al. Influence of Glycosylation on the Efficacy of an Env-Based Vaccine against Simian Immunodeficiency Virus SIVmac239 in a Macaque AIDS Model J. Virol., August 15, 2005; 79(16): 10386 - 10396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Chou, L. H. Huffman, R. Fu, A. K. Smits, and P. T. Korthuis Screening for HIV: A Review of the Evidence for the U.S. Preventive Services Task Force Ann Intern Med, July 5, 2005; 143(1): 55 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Monceaux, L. Viollet, F. Petit, R. H. T. Fang, M.-C. Cumont, J. Zaunders, B. Hurtrel, and J. Estaquier CD8+ T Cell Dynamics during Primary Simian Immunodeficiency Virus Infection in Macaques: Relationship of Effector Cell Differentiation with the Extent of Viral Replication J. Immunol., June 1, 2005; 174(11): 6898 - 6908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Goldstein, I. Ourmanov, C. R. Brown, R. Plishka, A. Buckler-White, R. Byrum, and V. M. Hirsch Plateau Levels of Viremia Correlate with the Degree of CD4+-T-Cell Loss in Simian Immunodeficiency Virus SIVagm-Infected Pigtailed Macaques: Variable Pathogenicity of Natural SIVagm Isolates J. Virol., April 15, 2005; 79(8): 5153 - 5162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Sanders, A. M. Bayoumi, V. Sundaram, S. P. Bilir, C. P. Neukermans, C. E. Rydzak, L. R. Douglass, L. C. Lazzeroni, M. Holodniy, and D. K. Owens Cost-Effectiveness of Screening for HIV in the Era of Highly Active Antiretroviral Therapy N. Engl. J. Med., February 10, 2005; 352(6): 570 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wasilk, J. D. Callahan, J. Christopher-Hennings, T. A. Gay, Y. Fang, M. Dammen, M. E. Reos, M. Torremorell, D. Polson, M. Mellencamp, et al. Detection of U.S., Lelystad, and European-Like Porcine Reproductive and Respiratory Syndrome Viruses and Relative Quantitation in Boar Semen and Serum Samples by Real-Time PCR J. Clin. Microbiol., October 1, 2004; 42(10): 4453 - 4461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. Haigwood, D. C. Montefiori, W. F. Sutton, J. McClure, A. J. Watson, G. Voss, V. M. Hirsch, B. A. Richardson, N. L. Letvin, S.-L. Hu, et al. Passive Immunotherapy in Simian Immunodeficiency Virus-Infected Macaques Accelerates the Development of Neutralizing Antibodies J. Virol., June 1, 2004; 78(11): 5983 - 5995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Rybarczyk, D. Montefiori, P. R. Johnson, A. West, R. E. Johnston, and R. Swanstrom Correlation between env V1/V2 Region Diversification and Neutralizing Antibodies during Primary Infection by Simian Immunodeficiency Virus sm in Rhesus Macaques J. Virol., April 1, 2004; 78(7): 3561 - 3571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G Hudgens, P. B Gilbert, and S. G Self Endpoints in vaccine trials Statistical Methods in Medical Research, April 1, 2004; 13(2): 89 - 114. [Abstract] [PDF]
|
|
|
|
|
|
M. Sagar, L. Lavreys, J. M. Baeten, B. A. Richardson, K. Mandaliya, B. H. Chohan, J. K. Kreiss, and J. Overbaugh Infection with Multiple Human Immunodeficiency Virus Type 1 Variants Is Associated with Faster Disease Progression J. Virol., December 1, 2003; 77(23): 12921 - 12926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. B. Campbell, K. Schneider, T. Wrin, C. J. Petropoulos, and E. Connick Relationship between In Vitro Human Immunodeficiency Virus Type 1 Replication Rate and Virus Load in Plasma J. Virol., November 15, 2003; 77(22): 12105 - 12112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Smith, S. Pentlicky, Z. Klase, M. Singh, C. Neuveut, C.-y. Lu, M. S. Reitz Jr., R. Yarchoan, P. A. Marx, and K.-T. Jeang An in Vivo Replication-important Function in the Second Coding Exon of Tat Is Constrained against Mutation despite Cytotoxic T Lymphocyte Selection J. Biol. Chem., November 7, 2003; 278(45): 44816 - 44825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. O'Connor, B. R. Mothe, J. T. Weinfurter, S. Fuenger, W. M. Rehrauer, P. Jing, R. R. Rudersdorf, M. E. Liebl, K. Krebs, J. Vasquez, et al. Major Histocompatibility Complex Class I Alleles Associated with Slow Simian Immunodeficiency Virus Disease Progression Bind Epitopes Recognized by Dominant Acute-Phase Cytotoxic-T-Lymphocyte Responses J. Virol., August 15, 2003; 77(16): 9029 - 9040. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Alter, G. Hatzakis, C. M. Tsoukas, K. Pelley, D. Rouleau, R. LeBlanc, J.-G. Baril, H. Dion, E. Lefebvre, R. Thomas, et al. Longitudinal Assessment of Changes in HIV-Specific Effector Activity in HIV-Infected Patients Starting Highly Active Antiretroviral Therapy in Primary Infection J. Immunol., July 1, 2003; 171(1): 477 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Nickle, M. A. Jensen, D. Shriner, S. J. Brodie, L. M. Frenkel, J. E. Mittler, and J. I. Mullins Evolutionary Indicators of Human Immunodeficiency Virus Type 1 Reservoirs and Compartments J. Virol., May 1, 2003; 77(9): 5540 - 5546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sutthent, N. Gaudart, K. Chokpaibulkit, N. Tanliang, C. Kanoksinsombath, and P. Chaisilwatana p24 Antigen Detection Assay Modified with a Booster Step for Diagnosis and Monitoring of Human Immunodeficiency Virus Type 1 Infection J. Clin. Microbiol., March 1, 2003; 41(3): 1016 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. DeVange Panteleeff, S. Emery, B. A. Richardson, C. Rousseau, S. Benki, S. Bodrug, J. K. Kreiss, and J. Overbaugh Validation of Performance of the Gen-Probe Human Immunodeficiency Virus Type 1 Viral Load Assay with Genital Swabs and Breast Milk Samples J. Clin. Microbiol., November 1, 2002; 40(11): 3929 - 3937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Chernoff The Significance of HIV Viral Load Assay Precision: A Review of the Package Insert Specifications of Two Commercial Kits J Int Assoc Physicians AIDS Care (Chic Ill), October 1, 2002; 1(4): 134 - 140. [Abstract] [PDF]
|
|
|
|
|
|
L. G. Kostrikis, G. Touloumi, R. Karanicolas, N. Pantazis, C. Anastassopoulou, A. Karafoulidou, J. J. Goedert, and A. Hatzakis Quantitation of Human Immunodeficiency Virus Type 1 DNA Forms with the Second Template Switch in Peripheral Blood Cells Predicts Disease Progression Independently of Plasma RNA Load J. Virol., September 11, 2002; 76(20): 10099 - 10108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Patel, M. T. Yu Kimata, J. E. Biggins, J. M. Wilson, and J. T. Kimata Highly Pathogenic Simian Immunodeficiency Virus mne Variants That Emerge during the Course of Infection Evolve Enhanced Infectivity and the Ability To Downregulate CD4 but Not Class I Major Histocompatibility Complex Antigens J. Virol., June 5, 2002; 76(13): 6425 - 6434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jennings, D. J. Brambilla, and J. W. Bremer Ratio of Two Successive Optical Densities from the Roche HIV-1 Monitor Test as a Measure of Accuracy of Estimates of Human Immunodeficiency Virus RNA Concentration J. Clin. Microbiol., March 1, 2002; 40(3): 1067 - 1068. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 |
Article
