Background Early in human immunodeficiency virus type 1 (HIV-1)infection there is a decline in viral replication that has beenattributed to host immunity, but the components of this response,particularly the ability of cytotoxic T lymphocytes to controlviral burden and influence the outcome of disease, are poorlyunderstood.
Methods We prospectively studied 33 patients with primary HIV-1infection for HIV-specific activated cytotoxic T lymphocytesand memory cytotoxic T lymphocytes and compared these lymphocyteresponses with changes in viral load and clinical status overthe subsequent 18 to 24 months.
Results Soon after infection, activated HIV-specific cytotoxicT lymphocytes, mediated primarily by CD8+ cells, were detectedin 17 of 23 patients (74 percent). Memory cytotoxic T lymphocyteswere found in 6 of 6 patients tested (100 percent) during thefirst three months of infection and in 17 of 21 patients (81percent) tested during the first six months. The frequenciesof memory cytotoxic T lymphocytes varied markedly over time,but overall they declined over the first 6 to 8 months and thenstabilized over the next 12 to 18 months. The patients withhigher frequencies of Env-specific memory cytotoxic T lymphocyteshad a median level of plasma HIV-1 RNA about one third thatof the patients with lower frequencies (median number of RNAcopies per milliliter, 22,000 vs. 62,000; P = 0.006). Patientswith low frequencies of Env-specific memory cytotoxic T lymphocytes(or none) in early infection had a more rapid decline to lessthan 300 CD4+ cells per cubic millimeter (P = 0.05).
Conclusions In early HIV-1 infection, the induction of memorycytotoxic T lymphocytes, particularly those specific for Env,helps control viral replication and is associated with slowerdeclines in CD4+ cell counts. Host cytolytic effector responsesappear to delay the progression of HIV-1 disease.
Without antiretroviral therapy, most people with human immunodeficiencyvirus type 1 (HIV-1) infection will have the acquired immunodeficiencysyndrome (AIDS) within a decade. Many clues about the pathogenesisof HIV-1 have come from the study of patients with unusuallyrapid or unusually slow progression of disease. Accumulatingevidence indicates that both host and viral factors affect diseaseprogression.1,2,3,4,5,6,7 Several studies, mostly cross-sectionalin design, have shown that host immunity to HIV-1 may be relatedto disease progression.8,9,10,11 In particular, HIV-1–specificcytotoxic T lymphocytes decrease in frequency over time, andpersons with detectable cytotoxic T lymphocytes tend to havestable clinical disease. In contrast, more recent studies showthat higher plasma levels of HIV-1 RNA are the strongest independentpredictors of progression to AIDS and death.12,13,14
Primary infection is typically associated with initially highlevels of plasma HIV-1 RNA that subsequently decline. HIV-1–specificcytotoxic T lymphocytes can appear early, even before seroconversion,and their emergence may coincide with a decline in viral load.15,16Exceptions have been found,17 however, and it has been arguedthat the decline in viremia is largely attributable to the lackof available CD4+ target cells for infection.18 After approximatelysix months of infection, plasma viremia reaches a quasi–steady-statelevel,12,13,14 and it has been hypothesized that host immunitymust have a critical role in achieving that equilibrium.19,20Thus, the critical events governing the variability in diseaseprogression must include both viral replication and immune responses,and it is likely that these may be determined in early infection.
We undertook a prospective study of 33 patients with primaryHIV-1 infection to determine the extent to which the responsesof cytotoxic T lymphocytes induced during this critical earlyperiod are associated with the level of viral replication overthe first one to two years and their relation to the subsequentcourse of disease.
Methods
Study Patients
We studied the first 33 consecutive persons enrolled at thePrimary HIV Infection Clinic of the University of Washington.21Patients at risk who had HIV-related symptoms or tested HIV-positivefor the first time on routine testing were referred from theuniversity clinics, AIDS-prevention programs, jail facilities,and physicians in the community. A time of infection was assignedfor each patient that represented the first day of clinicalillness in 31 patients (94 percent) and the halfway point betweena negative and a positive serologic test for HIV-1 in 2 patients(6 percent). Five healthy, HIV-1–seronegative volunteersserved as controls in the assays of cytotoxic T lymphocytes.The Human Subjects Review Board of the University of Washingtonapproved all aspects of the study.
Patients were screened for HIV-1 antibodies as previously described.21Plasma HIV-1 RNA levels were determined by the branched-chainDNA amplification method22; the lower level of sensitivity ofthe assay was 10,000 copies per milliliter. The HIV-1 titerin peripheral-blood mononuclear cells was measured by quantitativecell microculture.23 T-cell subgroups were counted by flow cytometry.21
Assays of Cytotoxic T Lymphocytes
Vectors containing recombinant vaccinia virus were used to expressHIV-1 or control gene products. The recombinant vaccinia virusencoding HIV-1LAIenv (vPE-16),24 HIV-1LAIgag (vDK-1),25 HIV-1LAIpol (vRT),26 and lacZ (vSC-8, used as a control)27 were obtainedthrough the AIDS Research and Reference Reagent Program (NationalInstitute of Allergy and Infectious Diseases, Bethesda, Md.).The recombinant vaccinia virus encoding the HIV-1LAI gene productsEnv, Gag, and Pol (vEGP) was kindly provided by D. Panacali(Therion Biologics, Cambridge, Mass.).
Activated cytotoxic T lymphocytes were measured in the firstconsecutive 21 volunteers and in 6 other volunteers enrolledsoon thereafter, on the basis of the availability of autologousB-lymphoblastoid cell lines. Fresh peripheral-blood mononuclearcells and CD4- and CD8-enriched T cells were used as effectorcells. To enrich the cell population for T-cell subgroups andremove natural killer cells, the peripheral-blood mononuclearcells were incubated with anti–Leu-11 (CD16) and eitheranti–Leu-2A (CD8) or anti–Leu-3A (CD4) monoclonalantibodies (Becton Dickinson, San Jose, Calif.), and were thennegatively selected after incubation with goat antimouse IgG–coatedbeads (Dynal, Lake Success, N.Y.). The purity of the T-cellsubgroups, as determined by flow cytometry, ranged from 92 to98 percent.
Autologous Epstein–Barr virus (EBV)–transformedB-lymphoblastoid cell lines were established from donor peripheral-bloodmononuclear cells28 and infected with recombinant vaccinia virus.K562 cells (American Type Culture Collection CCL243) servedas targets to measure the lytic activity of natural killer cells.Target cells labeled with chromium-51 and effector cells weredistributed into 96-well round-bottomed plates (Costar, Cambridge,Mass.) in triplicate, and the chromium-release assay was performed.29The spontaneous release of chromium-51 was less than 25 percentin all experiments. HIV-1–specific lysis was determinedby calculating the difference between the percentage of lysisof target cells expressing the HIV-1 gene product and that ofthe target cells infected with vSC-8; lysis of 10 percent ormore was considered positive. The responses were considerednegative if the HIV-1 and natural-killer lytic activities inthe undepleted peripheral-blood mononuclear cells were bothgreater than 10 percent but HIV-specific lysis in the populationsenriched with CD4, CD8, or both was less than 10 percent.
The frequencies of precursor cytotoxic T lymphocytes were measuredby limiting-dilution assay in 30 consecutively enrolled volunteers,including 6 enrolled within the first 90 days after infectionand 21 enrolled in the first 6 months. Adherent autologous monocyteswere infected with vEGP, irradiated with ultraviolet and gammaradiation, and used as stimulator cells.29 Serial dilutionsof fresh peripheral-blood mononuclear cells in RPMI with 10percent heat-inactivated human AB serum (Biocell, Rancho Dominguez,Calif.) were plated in 96-well round-bottomed plates in 24-wellreplicates. Stimulator cells (1000 cells), irradiated autologousperipheral-blood mononuclear cells (50,000 cells), and 20 Uof human recombinant interleukin-2 (Chiron, Emeryville, Calif.)were added to each well. The cultures were incubated at 37°Cin 5 percent carbon dioxide and provided with fresh medium ondays 3 and 7. On day 10, the cells from each well were dividedequally into four wells and tested to determine the lysis of5000 radiolabeled autologous target cells previously infectedwith vPE-16, vDK-1, vRT, or vSC-8. Sixteen wells of each ofthe four infected target cells were incubated with medium, and16 wells were incubated with 5 percent Triton-X, to determinethe spontaneous and maximal release of chromium, respectively.After a four-hour incubation at 37°C, the supernatants wereharvested and the release of chromium was measured. The spontaneousrelease was less than 20 percent of the maximal release, witha standard deviation of less than 15 percent in the replicatewells. In wells associated with lysis that exceeded the meanspontaneous release by 3 SD, the results were considered positive.The frequencies of memory cytotoxic T lymphocytes were estimatedfrom the initial number of responder cells at which 37 percentof the wells were negative for cytotoxicity on the basis ofthe single-hit Poisson model.30 The calculations were performedon the basis of the chi-square minimization method31 with software32kindly provided by Dr. C. Orosz (Ohio State University, Columbus).
Statistical Analysis
Descriptive statistics (medians, ranges, and percentages ofpatients with positive results) were used to summarize the data.When the measures of cytotoxic T lymphocytes were plotted againstthe time since infection, all the observations in one personwere connected by dashed lines to show the within-person andbetween-person variability. The overall trends were characterizedby a solid, smooth line generated by the loess procedure.33
Because of restrictions in the available volume of blood, measurementsof frequencies of memory cytotoxic T lymphocytes and viral loador CD4+ counts in the same blood sample were available for onlyone third of the data set. Therefore, to explore the relationbetween memory cytotoxic T lymphocytes and the viral load orCD4+ count, we paired each observation of memory cytotoxic Tlymphocytes with the closest measurement of viral load or CD4+cells, within a range of three weeks. This increased the percentageof paired measurements to 86 percent. Spearman's rank-correlationcoefficient was used to describe the strength of the associationbetween the frequency of memory cytotoxic T lymphocytes andthe viral load or CD4+ count. A bootstrap procedure (in whichpersons rather than observations were resampled) was used toassess the significance of the correlation coefficients.34 Generalizedestimating equations were used to compare log RNA levels aboveand below the median frequency of memory cytotoxic T lymphocytes,or 5 per million peripheral-blood mononuclear cells.
Patients for whom measurements of memory cytotoxic T lymphocyteswere available within the six-month period after infection (19of the 30 patients for whom data on cytotoxic T lymphocyteswere available) were classified as having either high or lowfrequencies of Env-specific memory cytotoxic T lymphocytes.The frequency was high if the first measurement was above thesmoothed line for trend, and low if the measurement was on orbelow that line. Kaplan–Meier methods were then used tocompute the time to the first CD4+ cell count of less than 300cells per cubic millimeter for the patients in these two groups,and a log-rank test was used to compare the two curves. Allcalculations of P values were two-tailed.
Results
Study Patients
Thirty-three adults with primary HIV-1 infection (median age,33 years; one patient was female) were studied over the firsttwo years of their infection. The demographic and clinical characteristicsof this group were similar to those of the larger cohort previouslydescribed.21 The median time of enrollment was 55 days afterHIV-1 infection, and the median CD4 count was 568 cells percubic millimeter (Table 1). No patient reported use of antiretroviraldrugs at enrollment, and only 15 percent received treatmentduring the subsequent months. Ninety-four percent of the patientswith acute infection had symptoms (Table 1). The median intervalfrom the onset of symptoms to the first analysis of cytotoxicT lymphocytes was 61 days.
Table 1. Clinical Variables in the 33 Patients with Primary HIV-1 Infection.
HIV-Specific Activated Cytotoxic T Lymphocytes
Fresh peripheral-blood mononuclear cells obtained from 23 patientssoon after presentation (median, 61 days after infection) weretested for their ability to recognize target cells expressingHIV-1 gene products. Activated HIV-specific cytotoxic T lymphocyteswere detected in 17 of these patients (74 percent) (Figure 1A).The HIV-specific lysis ranged from 10 to 26 percent among respondingpatients at an effector:target cell ratio of 100:1, and it wasless than 10 percent in the five HIV-1–seronegative controldonors (Figure 1A). The most common gene product to be recognizedinitially was HIV-1 Env, found in 94 percent of the patientswith positive responses; by contrast, HIV-1 Gag and Pol wererecognized less frequently, in 29 percent and 12 percent, respectively(Figure 1A).
Figure 1. Responses of Activated Cytotoxic T Lymphocytes to Specific HIV-1 Gene Products.
Panel A shows the responses of activated cytotoxic T lymphocytes in 23 patients with primary HIV-1 infection who were tested a median of 61 days after the infection and in 5 HIV-uninfected controls. Freshly isolated effector peripheral-blood mononuclear cells were tested without in vitro stimulation to assess the lysis of autologous target cells infected with vPE-16 (Env), vDK-1 (Gag), vRT (Pol), or vSC-8 (control) at an effector:target ratio of 100:1. Panel B shows the proportion of patients with primary HIV-1 infection who had activated cytotoxic-T-lymphocyte responses to autologous target cells expressing HIV-1 Env, Gag, or Pol during four periods over the course of infection. The number of patients studied in each period is shown below the graph.
Activated cytotoxic T lymphocytes were mostly mediated by CD8+effector cells, observed in 9 of 19 patients (47 percent) atan effector:target ratio of 25:1. The CD8+ effectors primarilyrecognized Env-expressing targets in these patients (in eightpatients, or 42 percent); they recognized Gag-expressing (inthree patients, or 16 percent) and Pol-expressing (in one patient,or 5 percent) targets less often. CD4+ effector cells were alsodetected in 4 of 18 patients (22 percent). The natural-killer–specificlysis was less than 10 percent among effector-cell populationswith either CD8+ or CD4+ HIV-1–specific cytolysis. Furthermore,low-level lysis of mismatched target cells was easily distinguishablefrom the lysis of autologous targets expressing HIV-1 Env infour patients (data not shown), indicating that the cytotoxicactivities were unlikely to represent antibody-dependent cellularcytotoxicity but instead represented major-histocompatibility-complex–restrictedcytotoxic T lymphocytes.
The frequency of patients with activated cytotoxic-T-lymphocyteeffector cells was similar when the patients were studied atintervals of three to six months (Figure 1B). The predominantactivated cytolytic responses were again Env-specific: overthe one-to-two-year period, 70 to 80 percent had detectableEnv-specific cytotoxic T lymphocytes, whereas less than 50 percenthad Gag-specific or Pol-specific responses (Figure 1B). Amongpatients in whom concurrent measurements of activated and memorycytotoxic T lymphocytes were made, activated cytotoxic T lymphocyteswere detected only when memory responses were present.
Frequencies of HIV-Specific Memory Cytotoxic T Lymphocytes
The frequencies of HIV-1–specific memory cytotoxic T lymphocytesreached peak levels during primary infection and declined overthe next 200 to 300 days (Figure 2 ). All six patients testedduring the first 90 days of infection had Env- and Gag-specificresponses. When examined at intervals of three to six months,over 80 percent had detectable HIV-1–specific cytotoxicT lymphocytes. The frequencies of memory cytotoxic T lymphocytesper million peripheral-blood mononuclear cells ranged from 0to 446 for Env, 0 to 333 for Gag, and 0 to 364 for Pol (Figure 2).By contrast, the frequencies of memory cytotoxic T lymphocytesspecific for HIV-1 Env, Gag, and Pol were less than 0.1 permillion in peripheral-blood mononuclear cells from five healthyHIV-seronegative donors on repeated testing. The precursor frequenciesmeasured in assays with the control targets infected with thevSC-8 were less than 3 memory cytotoxic T lymphocytes per millionperipheral-blood mononuclear cells in all patients studied.The coefficient of variation for the frequencies of memory cytotoxicT lymphocytes against the same HIV-1 gene product was less than12 percent (range, 3 to 11 percent). Repeated measurements offrequencies over time in a given person revealed considerablevariability, as Figure 2 shows. More often, cytotoxic-T-lymphocyteprecursors specific for one gene product predominated, particularlythose for HIV-1 Env. In some cases, the predominant gene productrecognized early was replaced by another over time (data notshown).
Figure 2. Longitudinal Analysis of Memory Cytotoxic T Lymphocytes during the 800 Days after Infection.
Each data point represents a measurement of the frequency of cytotoxic T lymphocytes (per million peripheral-blood mononuclear cells [PBMC]) against autologous target cells expressing HIV-1 Env, Gag, and Pol. The dashed lines connect three or more measurements in each patient. The solid lines showing overall trends were drawn through the data with use of the loess procedure (see the Methods section).
Correlation of Memory Cytotoxic T Lymphocytes with Viral Load
To determine whether the cytolytic responses in patients withprimary infection correlated with the concurrent viral load,we paired the log10-transformed frequencies of memory cytotoxicT lymphocytes with measurements of HIV-1 RNA in plasma and peripheral-blood-mononuclear-cell–associatedinfectious HIV-1 from blood collected the same day or withina range of three weeks (Table 2). There was an overall inversecorrelation between the frequencies of Env-specific memory cytotoxicT lymphocytes and plasma HIV-1 RNA (P = 0.02) and infectiousvirus (P = 0.1). A similar trend was found between the frequenciesof Gag-specific memory cytotoxic T lymphocytes and infectiousvirus (P = 0.06) but not plasma HIV-1 RNA (P = 0.22) (Table 2).When the data were stratified into three time periods (lessthan 6 months, 6 to 12 months, and more than 12 months afterinfection), the strongest inverse correlation, albeit not astatistically significant one, between Env-specific memory cytotoxicT lymphocytes and viral load was seen after 12 months of infection.
Table 2. Rank Correlation between the Frequency of Precursor Cytotoxic T Lymphocytes and the Viral Load and CD41 Count.
To ascertain the magnitude of the effect of cytotoxic T lymphocyteson viral load throughout the study period, median plasma HIV-1RNA levels (either concurrent ones or the closest within threeweeks) were compared with the frequencies of memory cytotoxicT lymphocytes that fell either above or at or below the overallmedian level of memory cytotoxic T lymphocytes (5 per millionperipheral-blood mononuclear cells) (Table 3). The number ofcopies of HIV-1 RNA per milliliter was significantly lower inthe group with higher frequencies of Env-specific cytotoxicT lymphocytes (median, 22,000) than in those with lower frequencies(median, 62,000; P = 0.006). Thus, higher frequencies of Env-specificmemory cytotoxic T lymphocytes were associated with, on average,one third the level of plasma RNA that was observed in patientswith lower frequencies.
Table 3. Plasma HIV-1 RNA Levels in Patients Stratified According to the Overall Frequency of Precursor Cytotoxic T Lymphocytes (pCTL).
Correlation of Cytotoxic T Lymphocytes with CD4+ Counts and Disease Progression
We performed a similar analysis comparing concurrent measurementsof frequencies of memory cytotoxic T lymphocytes and CD4+ cellcounts (Table 2). There was a trend toward higher frequenciesof Env-specific but not Gag- or Pol-specific memory cytotoxicT lymphocytes correlating with overall higher CD4+ cell counts(P = 0.09).
We next studied the relation between frequencies of memory cytotoxicT lymphocytes and disease progression, as evidenced by decliningCD4+ cell counts. We divided the patients into two groups accordingto whether the response of memory cytotoxic T lymphocytes washigh or low in the first six months after infection and comparedthe groups' CD4+ counts over time (see the Methods section).After 18 months, 8 of the 19 patients in whom measurements ofmemory cytotoxic T lymphocytes were available (42 percent) haddeclines in their CD4+ counts to less than 300 cells per cubicmillimeter (Figure 3). Among these 19 patients, 80 percent ofthose with initial Env-specific responses maintained CD4+ countsgreater than 300 cells per cubic millimeter, as compared withonly 44 percent of those without such responses (P = 0.05).The majority of the difference was apparent within the firstsix months of infection. After 18 months, the patients whoseinitial frequencies of Env-specific memory cytotoxic T lymphocyteswere higher had on average 90 more CD4+ cells per cubic millimeterthan those with lower frequencies, although the difference wasnot statistically significant.
Figure 3. Kaplan–Meier Analysis of Cumulative Rates of Progression to a CD4+ Count of 300 Cells or Fewer per Cubic Millimeter in 19 Patients with High and Low Levels of Response of Cytotoxic T Lymphocytes to HIV-1 Env in the Six Months after Infection.
In this analysis, the patients were stratified according to whether the first measurement of the Env-specific cytotoxic-T-lymphocyte response was above or below the smooth trend line shown in Figure 2.
Discussion
Although several studies have suggested that cytolytic responsesplay a key part in controlling HIV-1 infection, this study provideslongitudinal data on the frequency and kinetics of the cytotoxic-T-lymphocyteresponse after HIV-1 infection, as well as the temporal relationbetween cytotoxic T lymphocytes, viral load, and the declinein CD4+ cells. Our study clearly shows that in early HIV-1 infectionthere is a profound induction of virus-specific cytotoxic Tlymphocytes and that the levels of these responses decreasegradually and stabilize within the first year of infection.This pattern resembles the overall trends in viral load butoccurs slightly later. In addition to the fluctuations we observedin the overall frequencies of memory cytotoxic T lymphocytes,there was remarkable variation in the individual responses whenmeasurements were repeated over time.
To assess the magnitude and kinetics of memory cytotoxic T lymphocytesin early infection, we used a limiting-dilution assay that didnot stimulate detectable in vitro primary cytotoxic T lymphocytes,averted the concurrent expansion of nonspecific effector cells,and was reproducible when the same specimen was measured repeatedly.Comparative studies in our laboratory indicate that this methodresults in frequencies of memory cytotoxic T lymphocytes asmuch as 1 to 2 log lower than previously reported methods.9,10,35Although we restricted our analysis to the recognition of epitopesof HIV-1LAI expressed on target cells, the response patternsmight have been different if we had used epitopes from moredivergent or autologous strains.
This study demonstrates the predominance of Env-specific cytotoxicT lymphocytes in early infection, a finding consistent withprevious reports.16,36,37 These results suggest that in earlyinfection HIV-1 envelope epitopes may be immunodominant andthat over time, in association with virus variation and escape,the repertoire of cytotoxic T lymphocytes may broaden as otherepitopes exert greater pressure on the immune system. The evolutionof virus-specific cytotoxic T lymphocytes actually parallelsthe patterns of viral diversity that have been described inhomosexual men (the principal risk group in this study), inwhich the early viral populations are relatively homogeneouswithin the envelope region.38 Thus, Env-specific cytotoxic Tlymphocytes may contribute the major effector responses in patientssoon after the acquisition of HIV-1 infection.
Our findings indicate that higher frequencies of HIV-1 Env-specificand to a lesser extent Gag-specific cytotoxic T lymphocytescorrelate with lower levels of plasma HIV-1 RNA and peripheral-blood-mononuclear-cell–associatedinfectious virus. When we studied specific periods after infectionto understand when this effect is strongest, the correlationwas not found in the early period (up to six months after infection),when typically there are marked changes in measurements of bothmemory cytotoxic T lymphocytes and viral load, but it becamemore apparent as time passed. Although the magnitude of theresponse of cytotoxic T lymphocytes in reducing viral load wasless than that achievable with potent antiretroviral therapy,we believe a reduction in plasma HIV-1 RNA by a factor of nearlythree is not trivial. Moreover, such an effect, if sustained,can have prognostic implications with respect to rates of CD4decline and disease progression.13
These analyses do not prove that the cytolytic effector cellsdetected by an in vitro assay are actually destroying virus-infectedcells in vivo. However, there is evidence in other viral diseasesthat such activity does correlate with in vivo antiviral responsesor the disease course,39,40,41 through either direct lysis ofinfected cells or the release of antiviral cytokines. Why cytotoxicT lymphocytes directed specifically to the HIV-1 envelope areassociated with lower viral loads is not known, but perhapsthese lymphocytes have greater avidity for virus-infected cells.Alternatively, the Env-specific cytotoxic T lymphocytes maybe mediated by both CD4+ and CD8+ effector cells,29 the combinationof which may provide two distinct pathways with which to recognizeand attack virus-infected cells.
Our findings indicate that virus-specific cytotoxic T lymphocytesmay contribute to the control of early HIV-1 infection by reducingthe viral load and slowing the progression of disease. Giventhe wide fluctuations in cytotoxic T lymphocytes and viral loadin a given person, particularly in the early months of infection,the correlation of cytotoxic-T-lymphocyte responses with viralload and the CD4 count is best seen longitudinally rather thancross-sectionally. Although the strongest effect of cytotoxicT lymphocytes appears later in the course of infection, futurestudies in patients identified very soon after their exposureto HIV-1 should give more insight into the effect of the earlyinduction of cytotoxic T lymphocytes on the long-term progressionof disease.
Supported by grants (AI 05065, AI 35605, AI 27757, and AI 26503)from the National Institutes of Health.
We are indebted to Dr. Stephen Kent and Dr. Stanley Riddellfor helpful discussions; to Lynn Harwick for assistance withthe preparation of the manuscript; and in particular to thestudy participants for devoting their time and efforts to makethis study possible.
Source Information
From the Departments of Medicine (L.M., T. Schacker, T. Shea, L.C., M.J.M.) and Laboratory Medicine (L.C.), School of Medicine, and the Department of Biostatistics, School of Public Health (J.H.), University of Washington; and the Division of Clinical Research, Fred Hutchinson Cancer Research Center (L.C., M.J.M.) — all in Seattle.
Address reprint requests to Dr. McElrath at the Fred Hutchinson Cancer Research Center, Program in Infectious Diseases, M115, 1124 Columbia St., Seattle, WA 98104.
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[Abstract]
-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol 1985;5:3403-3409. 
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