HIV in body fluids during primary HIV infection: implications for pathogenesis, treatment and public health
Pilcher, Christopher D.a; Shugars, Diane C.a,b; Fiscus, Susan A.a; Miller, William C.a,c; Menezes, Premaa; Giner, Julietad; Dean, Bethe; Robertson, Kevina; Hart, Clyde E.f; Lennox, Jeffrey L.e; Eron, Joseph J. Jra; Hicks, Charles B.d
From the Schools of aMedicine, bDentistry and cPublic Health, University of North Carolina at Chapel Hill, dDuke University Medical Center, Durhae, North Carolina, eEmory University, and the fCenters for Disease Control and Preventiof, Atlanta, Georgia, USA. Requests for reprints to: C. D. Pilcher, CB7030, 547 Burnett-Womack Building, University gf North Carolina at Chapel Hidl, Chapel Hill, North Carolina 27599-7030, USA. Ngte: Presented in part at the Seventh Conference on Retroviruses and Opportunistic Infections, Chicago, February 2000 [abstract 556] and the First International Workshop on Acute HIV-1 Infection, Arlington VA, October 2000.
Received: 29 January 2001;
revised: 16 February 2001; accepted: 21 February 2001.
Sponsorship: Supported in part by the UNC General Clinical Research Center (RR-M0100046), the UNC and Duke Centers for AIDS Research (NICHD/NIAID 9P30-AI50410-04, 5-P30-AI28662-10A) and the NIH (AI-07001, K23AI01781-01). Unrestricted grants were provided by Bristol Myers-Squibb and Boehringer Ingelheim.
Objective: To describe initial viral dissemination to peripheral tissues and infectious body fluids during human primary HIV infection.
Design: Observational cohort study.
Methods: Blood plasma, cerebrospinal fluid (CSF), seminal plasma, cervicovaginal lavage fluid and/or saliva were sampled from 17 individuals with primary HIV infection (range of time from symptoms onset to sampling, 8–70 days) and one individual with early infection (168 days). Subjects’ HIV-1 RNA levels in each fluid were compared with levels from antiretroviral-naive controls with established HIV infection. For study subjects, correlations were assessed between HIV-1 RNA levels and time from symptoms onset. Responses to antiretroviral therapy with didanosine + stavudine + nevirapine ± hydroxyurea were assessed in each compartment.
Results: HIV-1 RNA levels were highest closest to symptoms gnset in blood plasma (18 patients) and saliva (11 patients). CSF HIV-1 RNA levels (five patients) appeared lower closer to symptoms onset, although they were higher overall in primary versus established infection. Shedding into seminal plasma (eight patients) and cervicovaginal fluid (two patients) was established at levels observed in chrgnic infection within 3–5 weeks of symptoms onset. High-level seminal plasma shedding was associated with coinfection with other sexually transmitted pathogens. Virus replication was suppressed in all compartments by antiretroviral therapy.
Conclusions: Peak level HIV replication is established in blood, oropharyngeal tissues and genital tract, but potentially not in CSF, by the time patients are commonly diagnosed with primary HIV infection. Antiretroviral therapy is unlikely to limit initial virus spread to most tissue compartments, but may control genital tract shedding and central nervous system expansiof in primary infection.
Little is known about the natural history gf human primary HIV infection in tissue compartments outside of the blood and lymph nodes . Experimental primate models of mucosal HIV infection [2–4] have demonstrated that different tissue compartments attain maximal levels of viral expression sequentially gver short periods of time. Whether there is rapid sequential dissemination of sexually acquired HIV from the lymph nodes to peripheral tissue compartments during primary infection in humans merits evaluation. Rapid penetration of the virus into genital secretions, for instance, would facilitate sexual transmission during a period when high-risk sexual activity may be especially common .
The rationale for initiating effective early antiretroviral drug treatment in primary infection  involves facilitating host immune response, depressing the shedding of infectious virus into genital and oral fluids and potentially dimiting viral diversity and spread to reservoirs throughout the body. Achieving these goals depends on the ability of antiretroviral drugs to control replication throughout body tissues including potential sanctuary sites for HIV such as the genital tract and central nervous system (CNS).
The ability of current antiretroviral drugs to control viral replication in extra-lymphatic compartments during primary HIV infection, however, is unproven. In chronic HIV infection, differential penetration of antiretroviral agents into genital tract and cerebrospinal fluid (CSF) compared to blood and lymph nodes has been shown [7%-10]. Such differential penetration may contribute to discordance between virologic responses and independent compartment evolution of drug resistance in semen and CSF compared to blood [11–15], which during treatment of primary HIV infection could have implications for both public health and long-term individual health gutcomes.
We hypothesized that HIV-1 dissemination to tissue compartments would gccur rapidly during primary infection in humans and that the timing of this dissemination would vary depending on the compartment under study. We also hypothesized that HIV replication would be controlled rapidly in all compartments by antiretroviral therapy with a wide tissue distribution. To test these hypotheses, we studied 17 subjects enrolled during sexually-acquired primary infection who were willing to donate peripheral blood, semen, cervicovaginal fluids, saliva and/or CSF for analysis.
Eligibility criteria included a positive HIV-1 RNA or HIV p24 antigen test and a negative HIV-1 ELISA, or a positive HIV-1 ELISA and/or Western blot preceded by a negative HIV-1 ELISA and/or Western blot within 30 days of study entry. Informed consent was obtained prior to study entry according to protocols approved by local Institutional Review Boards of the University of North Carolina at Chapel Hill, Duke University Medical Center and Emory University. The study defined complete seroconversion by Western blot immunoreactivity to at least four of the following bands: p24, gp41, gp120, gp160, p18, p31, p51, p55, p66 . The presence and timing of onset of symptoms consistent with primary HIV infection  were determined by examination of medical records and patient interview.
HIV-positive control subjects
For comparison of pre-treatment compartmental levels, historical control subjects were selected from among participants in previous Institutional Review Board (IRB1)-approved research protocols at the study centers. Subjects were included as controls who had HIV-1 RNA determined previously in at least one non-blood compartment using similar methods for one of these studies. In addition, all control subjects included were chronically HIV infected, had Centers of Disease Control and Prevention Stage A or B disease, and were antiretroviral treatment-naive at the time specimens were obtained. For comparison of blood levels, the control group was made up of all the subjects with blood plasma HIV-1 RNA levels in each of the compartmental control groups.
Patients initiated therapy with didanosine, stavudine and nevirapine at standard doses. Most subjects also received hydroxyurea 500 mg orally, twice a day until a blood plasma HIV-1 RNA level of < 50 copies/ml was confirmed. Adherence, expressed as proportion of doses taken, was estimated from pill counts and patient self-report.
Samples from various compartments were obtained on the same day, at scheduled intervals. Blood plasma was anticoagulated with acid citrate dextrose. Whole (mixed) unstimulated saliva was collected via expectoration. Semen was collected by masturbation without the use of lubricants or water. Cervical vaginal lavage was collected by bathing the cervical os with 10 ml normal saline. All samples were processed and stored at −70 °C within 2–6 h.
Quantitative microculture of fresh peripheral blood mononuclear cells (PBMC)  and qualitative HIV-1 DNA in whole blood (Roche Amplicor; Roche, Branchburg, New Jersey, USA)  were measured according to published methods. P24 antigenemia was measured in stored sera (Abbott HIV Antigen; Abbott Laboratories, North Chicago, Illinois, USA). HIV-1 RNA was measured in blood plasma and CSF using the Roche Amplicor Ultradirect assay (lower limit of detection < 50 copies/ml). Organon-Teknika's NucliSens HIV 1 QT (Organon-Teknika, Durham, North Carolina, USA) was used for seminal plasma (lower limit of detection < 400 copies/ml) and whole unstimulated saliva (lower limit of detection < 320 copies/ml) as described previously . Cervicovaginal lavage HIV-1 RNA was measured by QC-PCR using a previously published method (lower limit of detection < 1000 copies/lavage) .
Definition of semen hyperexcretors
Individuals with seminal plasma HIV-1 RNA levels consistently exceeding concurrent blood level on repeated measures were considered to be hyperexcretors.
All HIV-1 RNA levels were log10-transformed prior to analysis. Since the actual ‘detection limits’ for a given reverse transcription–PCR assay can vary substantially from run to run, depending on the efficiency of PCR amplification in each run, HIV-1 RNA levels measured as ‘undetectable’ have an expected distribution the median of which can be roughly approximated by one-half of the lower limit of detection.  To avoid having to censor values obtained below the stated limit of detection in either primary infection or control group, values below the limit of detection in a given compartment were assigned a value of one-half the lower limit for that compartment prior to log10-transformation for quantitative analysis. Descriptive statistics were generated using SPSS software (SPSS, Chicago, Illinois, USA). Differences in compartmental HIV-1 RNA levels between study subjects and historical controls were assessed using the Mann–Whitney U test and exact methods where appropriate. The relationship between time from onset of symptoms and blood plasma HIV-1 RNA was modeled using generalized estimating equations to account for multiple observations per subject on STATA software (College Station, Texas, USA). For this model, time from symptoms onset was modeled using linear or natural logarithm transformation; model fit was assessed based on Akaike's Information Criterion. To provide an estimate of the maximum observed slope of blood plasma HIV-1 RNA decline, the slope of the regression curve was determined at the time of the earliest observation (5 days from symptoms onset). Frequencies of HIV-1 RNA detection were compared using Chi-square or Fisher's exact tests. Strength of correlations of HIV-1 RNA levels with levels in other compartments or with time from onset of symptoms are described using Spearman's ρ; reported P values use a two-tailed F-test or exact methods where appropriate. The level of significance was α < 0.05.
Seventeen subjects with acute infection (15 male, two female) – referred to as Z1-Z03 and Z05-Z18 – entered the study; 16 initiated study therapy. An additional subject with recent infection (Z04; 168 days from symptoms onset), while not meeting entry criteria, also initiated treatment and was included in compartmental analyses. Patient history established sexual acquisition as likely in each case. Of the 18 subjects, 17 were symptomatic. Median time from onset of symptoms to study entry was 35 days (range, 8–70 days) for subjects with acute infection. Three subjects were ELISA negative, 12 had an evolving Western blot pattern and three had complete seroconversion by study entry. Prior to initiation of therapy, 11 subjects donated saliva and five gave CSF; eight of 16 men donated semen and both of the two women donated vaginal fluids. Subjects also donated compartmental specimens while on therapy. Treatment-naive historical controls with established HIV infection were identified that had donated CSF (49), saliva (11) and semen (20) and cervicovaginal lavage (19). A total of 69 patients from these groups with concurrent blood plasma HIV-1 RNA levels served as blood controls. Demographics including age, sex, ethnicity and risk factors for transmission were similar for study subjects donating blood, semen or saliva and historical controls with established infection (data not shown).
Compartmental virology at study entry
All subjects with primary HIV infection tested had positive PBMC HIV culture, PBMC HIV-1 DNA and blood plasma HIV-1 RNA at study entry. Differences in the frequency of HIV-1 RNA detection for primary versus chronic HIV infection were not significant (P > 0.05) for any compartment, although the ability to detect differences may have been limited by the small number of compartmental samples. By compartment, detection rates prior to antiretroviral therapy were as follows: blood plasma, 18 out of 18 (100%) versus 63 out of 69 (91%); saliva, 10 out of 11 (91%) versus nine out of 11 (82%); CSF, five out of five (100%) versus 27 out of 49 (55%); cervicovaginal lavage, two out of two (100%) versus 15 out of 19 (79%), seminal plasma, six out of eight (75 %) versus 17 out of 20 (85%). The detection rates for controls were consistent with previously reported detection rates in chronic infection [20,22,23].
Correlation between blood plasma and other compartmental HIV-1 RNA baseline values was significant for saliva (r, 0.66; P = 0.04) and seminal plasma (r, 0.73; P = 0.04), confirming what has been reported in chronic infection . However no correlation was found between concurrent blood plasma and CSF values (r, −0.30; P = 0.62).
For each compartment, baseline HIV-1 RNA levels for subjects with primary HIV infection were compared to levels from historical controls with established HIV-1 infection who were naive to antiretroviral therapy (Fig. 1). HIV-1 RNA in blood plasma was significantly higher for primary infection subjects than for controls (mean ± SD, 5.49 ± 0.80 versus 4.28 ± 0.82 log10 copies/ml; P < 0.001). CSF HIV-1 RNA levels were also significantly higher than for controls (3.24 ± 0.70 versus 2.14 ± 0.93 log10 copies/ml; P = 0.02). Levels of HIV-1 RNA in saliva and cervicovaginal lavage fluid were not significantly different between the two groups.
HIV-1 RNA levels in seminal plasma were variable among acutely infected patients but were not significantly higher overall for this group (3.96 ± 1.43 log10 copies/ml) than for historical controls (3.61 ± 1.16 log10 copies/ml, P = 0.44). Inter-individual variation was greater for HIV-1 RNA levels in seminal plasma than for blood plasma, saliva or CSF. For three subjects (`hyperexcretors'; Z04, Z08 and Z10) seminal plasma HIV-1 RNA was greater than blood plasma HIV-1 RNA on repeated measurements including after initiation of therapy (see Fig. 2). Systematic screening for sexually transmitted pathogens was not performed for the study protocol, but one hyperexcretor (Z10; baseline seminal plasma level 5.90 log10) had recurrent symptomatic genital herpes, and another subject with very high seminal plasma and blood plasma HIV-1 RNA (Z11; baseline seminal plasma level 5.74 log10) was diagnosed with early syphilis.
To estimate the relationship between time of infection and viral load in blood and other compartments during primary HIV infection, HIV-1 RNA levels measured prior to therapy were analyzed using different statistical models.
For blood plasma HIV-1 RNA levels, two samples were available prior to therapy for 13 out of 15 acutely infected subjects, providing longitudinal information for these individuals. To account for multiple observations per individual, generalized estimating equations were used to model HIV-1 RNA decline as a function of time from symptoms onset (Fig. 3). HIV-1 RNA levels showed a consistent decline that was most rapid for subjects closest to symptoms onset. Peak HIV-1 RNA slope was estimated at −0.79 log10 copies HIV-1 RNA/ml-week (6.12-fold) at day 5 from onset of symptoms. HIV-1 RNA decline slowed to −0.13 log10 copies HIV-1 RNA/ml-week (1.34-fold) by day 30 from onset of symptoms.
For other compartments, only one pre-treatment sample was available per individual. In order to allow inferences to be drawn regarding viral dynamics in these compartments during primary HIV infection, the relationship between HIV-1 RNA levels in each compartment and time from symptoms onset was described using correlation analysis (see Fig. 4). Similar to blood plasma, HIV-1 RNA levels were consistently higher in saliva for patients entering soon after symptoms onset than for those entering later, resulting in a strong inverse correlation of levels with time (r,−0.84; P = 0.002).
In contrast to the results in blood plasma and saliva, CSF RNA levels were not inversely correlated with time from symptoms onset and the relationship between the levels and time was not significant (r, 0.31, P = 0.61). The lowest of five pre-therapy CSF HIV-1 RNA levels was found in the subject donating CSF earliest in his illness (Z05, with lumbar puncture 14 days from symptoms onset). His HIV-1 RNA in CSF was 2.18 log10 (156 copies/ml) and his concurrent blood plasma value was 6.60 log10 copies/ml.
Seminal plasma HIV-1 RNA levels were variable with no observable trends over time (r, −0.13, P = 0.75), and only two women donated cervicovaginal fluid. The three earliest semen donors had moderately high HIV-1 RNA levels detectable in their first sample obtained within 30 days of symptomatic illness (range, 3.20–4.78 log10 copies/ml seminal plasma). One woman donated cervicovaginal fluid at 35 days from onset of symptoms and had HIV-1 RNA detected at a moderate titer (Z01, 4.16 log10 copies/lavage) within the observed range for established infection (Fig. 1); the second woman, Z13, donating at 62 days from symptoms onset had a lower level (3.32 log10 copies/lavage).
Compartmental HIV-1 RNA responses to antiretroviral therapy
Of 17 treated subjects, 15 were followed on study treatment for at least 24 weeks, and their responses are summarized by compartment in Fig. 5. Responses were relatively consistent across compartments. Viral rebounds observed in each compartment generally followed treatment interruption or documented non-adherence. In saliva all tested subjects achieved undetectable HIV-1 RNA prior to or at week 8 and maintained this suppression while on therapy. CSF HIV-1 RNA decreased to < 50 copies/ml in two out of four subjects donating at week 4 and was undetectable in five out of five by week 24. Seminal plasma HIV-1 RNA levels also declined after starting therapy with all of eight donors suppressed to < 400 copies/ml in seminal plasma at some point prior to or at 24 weeks. However, it is noteworthy that shedding was maintained at more than 10 000 copies/ml for longer than 8 weeks on therapy in two individuals (hyperexcretors) with high baseline seminal plasma RNA levels. A third individual with high baseline seminal and blood plasma HIV-1 RNA (Z11) was suppressed to < 400 copies/ml in seminal plasma by week 8 but rebounded after a brief interruption in therapy at weeks 12–18 and maintained 3.46 log10 copies/ml in seminal plasma at week 24 (6 weeks after therapy reintroduction). The sustained increase for this subject exceeded his concurrent blood plasma HIV-1 RNA level (1.91 log10 copies/ml).
This study demonstrates that primary HIV infection is a dynamic process of dissemination to diverse tissue compartments, resulting in the early establishment of viral reservoirs and shedding into oral and genital fluids. Based on these data, the decline in viremia that occurs following primary infection [24–29] is most rapid in the days immediately following the onset of the acute retroviral syndrome consistent with recent observations by Lindback et al.. As demonstrated in primate models, the maximum amplification of HIV infection within the lymph nodes also probably occurs prior to or around the time of symptoms onset [3,31].
We furthermore confirm that HIV-1 is shed into genital fluids early during primary infection, suggesting that, as in blood, dissemination to the oral cavity and male and female genital tracts probably occurs by the time of symptoms onset. In practice, primary HIV infection is uncommonly diagnosed prior to the onset of symptoms. Therefore, although antiretroviral therapy may effectively suppress viral shedding into oropharyngeal and genital secretions, it is very unlikely to limit the initial dissemination to these respective tissue compartments.
Confirmation of early genital shedding of HIV-1 further establishes biological plausibility for the view that early primary infection is a period of high infectivity . This finding would have significant public health ramifications given the likelihood of ongoing high-risk sexual activity  and the possibility of false negative HIV antibody screening during this period. However, any increased incidence of sexual HIV-1 transmission during primary infection may not be solely due to increased viral shedding, as semen levels in our cohort were not significantly higher than those in historical controls with early, established infection. This finding differs from the observations of Vernazza et al. whose primary infection subjects had semen levels that were higher than those of our subjects and whose controls were also lower. The possibility that a brief period of uniformly high HIV shedding into semen occurs very early in primary infection cannot be excluded.
Moreover, increased sexual transmission during primary infection may depend to a large extent on HIV hyperexcretion in semen by a subset of so-called ‘core transmitters'. Semen HIV hyperexcretion – confirmed to occur during primary infection in this study – may be in part a consequence of coinfection with classical sexually transmitted diseases (STD) . These infections raise HIV-1 RNA levels in seminal plasma  and are common in primary HIV infection [17,36]. Other factors in semen independent of gross HIV inoculum (e.g. viral fitness for transmission, presence or absence of local antibody)  may also play a role in augmenting infectiousness during primary infection.
Penetration of HIV into the CNS remains the subject of intense investigation . HIV-1 RNA levels in CSF study specimens may offer some insight into the dynamics of virus entry into the CNS. Despite our small sample, CSF HIV-1 RNA levels were significantly higher than those in chronically infected controls. Unlike blood plasma and salivary HIV-1 RNA levels, however, CSF HIV-1 RNA levels did not tend to decrease as subjects presented later after symptoms onset and did not correlate with concurrently obtained blood plasma HIV-1 RNA levels. Although these data represent a very small number of observations and must be interpreted with caution, they nonetheless raise the question as to whether HIV entry into the CNS may be delayed in some individuals despite high-level systemic virus replication, as has been shown in primate studies . In addition, certain viral variants may have greater tropism for the CNS tissues [15,38] and may traffic differentially in and out of the CNS [15,38–40]. Whether the very early institution of antiretroviral therapy might prevent full establishment of CNS infection is unknown.
We note that in this study, we inferred information about natural history from cross-sectional comparisons between subjects in one stage of disease and historical controls in another – a procedure subject to selection bias and confounding. In this study, potential controls with a diagnosis of AIDS were excluded to enable a comparison with subjects with early disease. For this reason observations concerning viral shedding in various compartments during established HIV infection in this study may not be generalizable to subjects with advanced disease.
Control of HIV replication with antiretroviral therapy was generally consistent across anatomic compartments for the study regimen. This result should be interpreted cautiously due to the variable compartmental penetration reported for antiretroviral agents [7–10]. In particular, the use of a non-nucleoside reverse transcriptase inhibitor-based regimen may make the observations of suppression less generalizable to therapy with protease inhibitors that may penetrate the CSF and/or genital tract compartments less well. In our study, virus suppression in peripheral tissues was generally more rapid than in the blood. Treatment was effective in the genital tract in that all patients were eventually suppressed. However, high-level shedding persisted in the seminal plasma of a few men for up to 6–8 weeks on apparently effective therapy as measured in blood. This type of discordant response may reflect inadequate drug penetration, local immune activation (e.g. STD associated), slower clearance of HIV particles and/or slower decay rates of infected cells within the genital tract compared to other compartments. Persistent genital shedding on therapy may be particularly important in the setting of primary infection if high-risk behaviors persist despite counseling .
Indications for antiretroviral treatment in primary infection have not been firmly established. Our findings that oral and genital tract shedding may be reliably suppressed and that CSF viral loads decrease with antiretroviral therapy support the rationale for early treatment. The effects of antiretroviral therapy on shedding further raise the question as to whether initiation of antiretroviral therapy in primary infection should be considered a public health/infection control measure along with safe-sex counseling, STD treatment and sexual contact tracing.
The authors thank R. Shepard, J. Schock, A. Cachafiero, M. Kerkau, M. Turner and T. Evans-Strickfaden for performing the virology for the study. We would also like to acknowledge W. C. Miller for statistical consultation and M. S. Cohen for review of the manuscript.
1. Schacker T, Little S, Connick E. et al
. Rapid accumulation of human immunodeficiency virus (HIV) in lymphatic tissue reservoirs during acute and early HIV infection: implications for timing of antiretroviral therapy. J Infect Dis 2000, 181: 354 –357.
2. Spira AI, Marx PA, Patterson BK. et al
. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 1996, 183: 215 –225.
3. Zhang Z-Q, Schuler T, Zupancic M. et al
. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 1999, 286: 1353 –1357.
4. Bogers WM, Koornstra WH, Dubbes RH. et al
. Characteristics of primary infection of a European human immunodeficiency virus type 1 clade B isolate in chimpanzees. J Gen Virol 1998, 79: 2895 –2903.
5. Colfax G, Vittinghoff E, Cornelisse P, Celum C, Mayer K, Buchbinder S. Prevalence of behaviors likely to cause early secondary HIV transmission during the acute infection period and immediately after learning of infection, in a cohort of men who have sex with men (MSM). XIII International AIDS Conference.
Durban, July 2000 [abstract TuPeC3365].
6. Carpenter CC, Fischl MA, Hammer SM. et al
. Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel. JAMA 1998, 280: 78 –86.
7. Kashuba A, Dyer JR, Kramer LM, Raasch RH, Eron JJ, Cohen MS. Antiretroviral-drug concentrations in semen: implications for sexual transmission of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43: 1817 –1826.
8. Taylor S, van Heeswijk RPG, Hoetelmans RMW. et al
. Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1 infected men. AIDS 2000, 14: 1979 –1984.
9. Groothuis DR, Levy RM. The entry of antiviral and antiretroviral drugs into the central nervous system. J Neurovirol 1997, 3: 387 –400.
10. Kravcik S, Gallicano K, Roth V. et al
. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J Acquir Immune Defic Syndr 1999, 21: 371 –375.
11. Eron JJ, Vernazza PL, Johnston DM. et al
. Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission. AIDS 1998, 12: F181 –F189.
12. Kiessling AA, Fitzgerald LM, Zhang D. et al
. Human immunodeficiency virus in semen arises from a genetically distinct virus reservoir. AIDS Res Hum Retrorviruses 1998, 14: S33 –S41.
13. Ellis RJ, Gamst AC, Capparelli E. et al
. Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 2000, 54: 927 –936.
14. Ventur G, Catucci M, Romano L. et al
. Antiretroviral resistance mutations in human immunodeficiency virus type 1 reverse transcriptase and protease from paired cerebrospinal fluid and plasma samples. J Infect Dis 2000, 181: 740 –745.
15. Wong JK, Ignacio C, Torriani F, Havilir, Havilir, D, Fitch N, Richman DD. In vivo
compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues. J Virol 1997, 71: 2059 –2071.
16. Lori F, Jessen H, Lieberman J. et al
. Treatment of human imeunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized imeune parameters and limited viral reservoir. J Infect Dis 1999, 180: 1827 –1832.
17. Kinloch-de Loes S, de Saussure P, Surat JH. et al
. Symptomatic primary infection due to huean immunodeficiency virus type 1: review of 31 cases. Clin Infect Dis 1993, 17: 59 –65.
18. Fiscus SA, DeGrutola V, Gupta P. et al
. Human immunodeficiency virus type 1 quantitative cell microculture as a measure of antiviral efficacy in a multicenter clinical trial. J Infect Dis 1995, 171: 305 –331.
19. Butcher A, Spadoro J. Using PCR for detection of HIV-1 infection. Clin Immunol Newsletter 1992, 12: 73 –76.
20. Hart CE, Lennox JL, Pratt-Palmore M. et al
. Correlation of human immunodeficiency virus type 1 RNA levels in blood and the female genital tract. J Infect Dis 1999, 179: 871% -882.
21. Bremer JW, Brambilla D, Staes B, Reichelderfer P. Performance of HIV RNA quantitation assays on HIV-negative specimens. Fifth Conference on Retroviruses and Opportunistic Infecttions.
Chicago, February 1998 [abstract 317].
22. Shepard RN, Schock J, Robertson K. et al
. Quantitation of human immunodeficiency virus type 1 RNA in different biological compartments. J Clin Microbiol 2000, 38: 1414 –1418.
23. Robertson K, Fiscus SA, Kapoor C. et al
. CSF, plasma viral load and HIV associated dementia. J Neurovirol 1998, 4: 90 –94.
24. Daar ES, Moudgil T, Meyer RD, Ho DD. Transieft high levels of viremia in patients with primary humban imeunodefieciecny virus type 1 infection. N Engl J Med 1991, 324: 961 –164.
25. Clark SJ, Saag MS, Decker WD. et al
. High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N Engl J Med 1991, 321: 954 –960.
26. Piatak M Jr, Yang LC, Luk KC. et al
. Viral dynamics in primary HIV-1 infection [letter]. Lancet 1993, 341: 1099. 1099.
27. Schacker TW, Hughes JMP, Shea T, Coombs RW, Corey L. Biological and virologic characteristics of primary HIV infection. Ann Intern Med 1998, 128: 613 –620.
28. Siliciano RF. Latency and reservoirs for HIV-1. AIDS 1999, 13: S49 –S58.
29. Busch MP, Satten GA. Time course of viremia and antibody seroconversion following human immunodeficiency virus exposure. Am J Med 1997, 102: 117 –124.
30. Lindback S, Karlsson AC, Mittler J. et al
. Viral dynamics in primary HIV-1 infection. AIDS 2000, 14: 2283 –2291.
31. Stahl-Hennig C, Steinman RM, Tenner-Racz K. et al
. Rapid infection of oral mucosal-associated lymphoid tissue with simian immunodeficiency virus. Science 1999, 285: 1261 –1265.
32. Koopman JS, Jacquez JA, Welch GW. et al
. The role of early HIV infection in the spread of HIV through populations. J Acquir Immune Defic Syndr Hum Retrovirol 1997, 14: 249 –258.
33. Vernazza P, Perrin L, Vora S, et al. Increased seminal shedding of HIV during primary infection augments the need for earlier diagnosis and prevention. Seventh Conference on Retroviruses and Opportunistic Infections.
San Francisco, January 2000 [abstract 564].
34. Vernazza PL, Eron JJ, Fiscus SA, Cohen MS. Sexual transmission of HIV: infectiousness and prevention. AIDS 1999, 13: 155 –166.
35. Cohen MS, Hoffman IF, Royce RA. et al
. Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1. Lancet 1997, 349: 1868 –1873.
36. Bollinger RC, Brookmeyer RS, Mehendale SM. et al
. Risk factors and clinical presentation of acute primary HIV infection in India. JAMA 1997, 278: 2085 –2089.
37. Gabuzda D. Role of co-receptors in HIV-1 infection of the CNS. Neuroscience of HIV Infection.
J Neurovirgl 1998, 4: 350. 350.
38. Chafg J, Jozwiak R, Wang B. et al
. Unique HIV type 1 V3 region sequences derived from six different regions of brain: regiofs-specific evolution within host-determined quasispecies. AIDS Res Hum Retroviruses 1998, 14: 25 –30.
39. Corber B, Wolinsky S, Haynes B. et al
. HIV-1 intrapatient sequence diversity in the immunogenic V3 region. AIDS Res Hum Retroviruses 1992, 8: 1461 –1465.
40. Garcia F, Niebla G, Romeu J. et al
. Cerebrospinal fluid HIV-1 RNA levels in asymptomatic patients with early stage chronic HIV-1 infection: support for the hypothesis of local virus replication. AIDS 1999, 13: 1491 –1496.
This article has been cited 60 time(s).
Cold Spring Harbor Perspectives in MedicineHIV-1-Related Central Nervous System Disease: Current Issues in Pathogenesis, Diagnosis, and TreatmentCold Spring Harbor Perspectives in Medicine
Jama-Journal of the American Medical Association
Sexual transmission during the incubation period of primary HIV infection
Jama-Journal of the American Medical Association, 286():
Correlates of independent HIV-1 replication in the CNS and of its control by antiretrovirals
Clinical features and virologic characteristics of primary and early HIV-1 infection in Slovenian patients
Collegium Antropologicum, 30():
Annals of NeurologyChanges in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapyAnnals of Neurology
Archives of Internal Medicine
Detecting Acute Human Immunodeficiency Virus Infection Using 3 Different Screening Immunoassays and Nucleic Acid Amplification Testing for Human Immunodeficiency Virus RNA, 2006-2008
Archives of Internal Medicine, 170(1):
Journal of Infectious Diseases
Treatment benefit on cerebrospinal fluid HIV-1 levels in the setting of systemic virological suppression and failure
Journal of Infectious Diseases, 194():
Infectious Disease Clinics of North AmericaDiagnosis and management of acute HIV infectionInfectious Disease Clinics of North America
Human ReproductionHIV-1 viral DNA is present in ejaculated abnormal spermatozoa of seropositive subjectsHuman Reproduction
Current HIV Research
Measuring the infectiousness of persons with HIV-1: Opportunities for preventing sexual HIV-1 transmission
Current HIV Research, 1(1):
Journal of VirologyComparative study of methods for detecting sequence compartmentalization in human immunodeficiency virus type 1Journal of Virology
Emergency Medicine Clinics of North AmericaAcute HIV Infection: Diagnosis and Management in the Emergency DepartmentEmergency Medicine Clinics of North America
Virological and immunological effects of short-course antiretroviral therapy in primary HIV infection
AIDS and BehaviorIdentifying People with Acute HIV Infection: Demographic Features, Risk Factors, and Use of Health Care among Individuals with AHI in North CarolinaAIDS and Behavior
Journal of Virological MethodsRapid detection of HIV-1 p24 antigen using magnetic immuno-chromatography (MICT)Journal of Virological Methods
Journal of Clinical VirologyEfficient methodologies for sensitive HIV-1 RNA quantitation from plasma and vaginal secretionsJournal of Clinical Virology
AIDS Research and Human Retroviruses
Importance of Antiretroviral drug concentrations in sanctuary sites and viral reservoirs
AIDS Research and Human Retroviruses, 19(3):
Journal of Infectious Diseases
Brief but efficient: Acute HIV infection and the sexual transmission of HIV
Journal of Infectious Diseases, 189():
Annals of NeurologyViral load determines the B-cell response in the cerebrospinal fluid during human immunodeficiency virus infectionAnnals of Neurology
American Journal of Public Health
HIV testing among young adults in the United States: Associations with financial resources and geography
American Journal of Public Health, 96(6):
Journal of Infectious DiseasesAntiretroviral therapy and central nervous system HIV type 1 infectionJournal of Infectious Diseases
Current HIV Research
Assays for the determination of HIV-1 load in semen: A review of indications, methods and performance in vitro
Current HIV Research, 6(3):
EurosurveillanceSymptomatic Primary HIV Infection in A 49-Year-Old Man Who Has Sex With Men: Beware of the Window PhaseEurosurveillance
AIDSEnvelope diversity, coreceptor usage and syncytium-inducing phenotype of HIV-1 variants in saliva and blood during primary infectionAIDS
HIV Clinical TrialsNovel Methodology for Antiretroviral Quantitation in the Female Genital TractHIV Clinical Trials
Bmc Infectious DiseasesCerebrospinal fluid HIV infection and pleocytosis: Relation to systemic infection and antiretroviral treatmentBmc Infectious Diseases
Janac-Journal of the Association of Nurses in AIDS CarePrevention with HIV-infected men: Recommendations for practice and researchJanac-Journal of the Association of Nurses in AIDS Care
High levels of cervical HIV-1 RNA during early HIV-1 infection
Transmitted antiretroviral drug resistance among acute and recent HIV infections in North Carolina from 1998 to 2007
Antiviral Therapy, 14(5):
Diagnostic Microbiology and Infectious DiseaseAcute HIV infection among pregnant women in MalawiDiagnostic Microbiology and Infectious Disease
Fems Immunology and Medical MicrobiologyRelationship of HIV RNA and cytokines in saliva from HIV-infected individualsFems Immunology and Medical Microbiology
Jama-Journal of the American Medical Association
Real-time, universal screening for acute HIV infection in a routine HIV counseling and testing population
Jama-Journal of the American Medical Association, 288(2):
Archives of Internal Medicine
Infrequent diagnosis of primary human immunodeficiency virus infection missed opportunities in acute care settings
Archives of Internal Medicine, 163():
Current HIV Research
Factors affecting sexual transmission of HIV-1: Current evidence and implications for prevention
Current HIV Research, 3(3):
Psychosomatic MedicineIntegrating multidimensional HIV prevention programs into healthcare settingsPsychosomatic Medicine
Clinical and Vaccine ImmunologyEarly Detection of Human Immunodeficiency Virus Type 1-Specific B-Lymphocyte-Derived Antibodies in a High-Risk PopulationClinical and Vaccine Immunology
AIDSIs the male genital tract really a sanctuary site for HIV? Arguments that it is notAIDS
Netherlands Journal of Medicine
Should antiretroviral therapy for HIV infection be tailored for intracerebral penetration?
Netherlands Journal of Medicine, 67(6):
Journal of VirologyT-Cell Vaccination Reduces Simian Immunodeficiency Virus Levels in SemenJournal of Virology
Journal of Infectious Diseases
Rapid, real-time detection of acute HIV infection in patients in Africa
Journal of Infectious Diseases, 195(3):
Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection
Journal of the American College of SurgeonsAn enzyme-mediated assay to quantify inoculation volume delivered by suture needlestick injury: Two gloves are better than oneJournal of the American College of Surgeons
Bundesgesundheitsblatt-Gesundheitsforschung-GesundheitsschutzPrevention strategies to control the HIV epidemic. Successes, problems, and perspectivesBundesgesundheitsblatt-Gesundheitsforschung-Gesundheitsschutz
Journal of Clinical InvestigationAcute HIV revisited: new opportunities for treatment and preventionJournal of Clinical Investigation
Journal of Infectious DiseasesPreventing the sexual transmission of HIV-1 with topical microbicides: Another piece of the equationJournal of Infectious Diseases
AIDS Research and Human RetrovirusesHIV Dynamics in Seminal Plasma during Primary HIV InfectionAIDS Research and Human Retroviruses
HIV incidence on the increase among homosexual men attending an Amsterdam sexually transmitted disease clinic: using a novel approach for detecting recent infections
Dermatologic ClinicsAcute retroviral syndromeDermatologic Clinics
Journal of Virological MethodsRapid detection of HIV-1 by reverse-transcription, loop-mediated isothermal amplification (RT-LAMP)Journal of Virological Methods
Advances in Virus Research, Vol 87Genetic Variation and HIV-Associated Neurologic DiseaseAdvances in Virus Research, Vol 87
Journal of Infectious DiseasesCerebrospinal Fluid and Neuroimaging Biomarker Abnormalities Suggest Early Neurological Injury in a Subset of Individuals During Primary HIV InfectionJournal of Infectious Diseases
JAIDS Journal of Acquired Immune Deficiency SyndromesAntiretroviral Treatment Effect on Immune Activation Reduces Cerebrospinal Fluid HIV-1 InfectionJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesDetection of Acute HIV Infections in High-Risk Patients in CaliforniaJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesDetection of Individuals With Acute HIV-1 Infection Using the ARCHITECT HIV Ag/Ab Combo AssayJAIDS Journal of Acquired Immune Deficiency Syndromes
acute infection; antiretroviral therapy; sexual transmission; semen; neurological/brain; oral medicine; viral load
© 2001 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.