Background In most subjects infected with human immunodeficiencyvirus type 1 (HIV-1), clinical or laboratory evidence of immunodeficiencydevelops within 10 years of seroconversion, but a few infectedpeople remain healthy and immunologically normal for more thana decade. Studies of these subjects, termed long-term survivors,may yield important clues for the development of prophylacticand therapeutic interventions against the acquired immunodeficiencysyndrome.
Methods and Results We studied 10 seropositive subjects whoremained asymptomatic with normal and stable CD4+ lymphocytecounts despite 12 to 15 years of HIV-1 infection. Plasma cultureswere uniformly negative for infectious virus. However, particle-associatedHIV-1 RNA was detected in four subjects with a sensitive branched-DNAsignal-amplification assay, whereas in five others the levelsof HIV-1 RNA were too low to detect. Infectious HIV-1 was detectedin peripheral-blood mononuclear cells (PBMC) of three subjectsby standard limiting-dilution cultures, and infectious viruswas recovered from another subject with use of a CD8-depletedculture. The other six subjects had no detectable infectiousvirus in their PBMC. A quantitative polymerase-chain-reactionassay revealed that all subjects had detectable but low titersof viral DNA in PBMC. Overall, the viral burden in the plasmaand PBMC of long-term survivors was orders of magnitude lowerthan that typically found in subjects with progressive disease.
There was no in vitro evidence of resistance by host CD4+ lymphocytesto HIV-1 infection. However, long-term survivors had a vigorous,virus-inhibitory CD8+ lymphocyte response and a strong neutralizing-antibodyresponse. In two subjects the kinetics of viral replicationwas consistent with the presence of a substantially attenuatedstrain of HIV-1.
Conclusions Subjects who remain asymptomatic for many yearsdespite HIV-1 infection have low levels of HIV-1 and a combinationof strong virus-specific immune responses with some degree ofattenuation of the virus.
The natural history and pathogenic processes of human immunodeficiencyvirus type 1 (HIV-1) infection are complex and variable, andthey depend on a multitude of viral and host factors and theirinteractions.1 Host factors may result in a variable susceptibilityto HIV-1 infection and its pathogenic effects, whereas variationin the virus may account for differences in virulence and diseaseprogression. Although symptoms related to the acquired immunodeficiencysyndrome (AIDS) or laboratory evidence of immunodeficiency developsin a majority of infected persons within 10 years of seroconversion,2,3,4,5a small number (approximately 5 percent) of infected persons,termed long-term survivors or persons with long-term nonprogressivedisease, have remained clinically healthy and immunologicallynormal for more than a decade.6,7,8,9,10,11 These long-termsurvivors have recently become the subject of intensive investigation,because they may yield important information on the determinantsof nonprogression that may be useful in designing new interventionalstrategies to contain the disease.
To obtain a balanced view of the pathogenic processes in long-termsurvivors, we examined host, immunologic, and virologic factorsin a cohort of 10 subjects who have remained asymptomatic withnormal and stable CD4+ lymphocyte counts despite 12 to 15 yearsof HIV-1 infection.
Methods
Study Subjects
Ten HIV-1–seropositive subjects from the New York metropolitanarea were referred to us because they met our working definitionof long-term survivors of HIV-1 infection: they had no symptoms,normal and stable CD4+ lymphocyte counts, no prolonged use ofantiretroviral agents, and at least 12 years of infection. Thegeneral clinical characteristics of the cohort are summarizedin Table 1. The subjects ranged in age from 38 to 47 years,and all but one were men. Seven were infected through homosexualcontact, two were infected through intravenous drug use, andthe one woman was infected heterosexually. Their CD4+ lymphocytecounts have been consistently in the normal range, with no declineover time. The duration of HIV-1 infection was documented bythe date of seroconversion in three subjects (Subjects 1, 4,and 9) who participated in a prospective study of the naturalhistory of the disease at the New York Blood Center. Subject7 had given birth to an infected child 13 years before the startof our study, and Subject 8 had had unexplained hypergammaglobulinemiaand lymphoid hyperplasia on biopsy 15 years before the studybegan. The duration of infection in the other subjects was determinedon the basis of the year in which they discontinued high-riskbehavior, such as intravenous drug use (Subjects 2 and 5) orunprotected homosexual sex (Subjects 3, 6, and 10). None hadreceived antiretroviral agents for a prolonged period, althoughsome had received short courses of zidovudine (Subjects 2 and7), didanosine (Subject 2), or recombinant gp160 (Subject 3).No subject was receiving antiretroviral therapy at the timeof this study. As Table 1 shows, these long-term survivors hada range of HLA class I and II phenotypes as determined by standardserologic typing (Blood Systems Laboratory, Scottsdale, Ariz.),indicating that they did not share a common HLA type. In addition,the 10 subjects were not found to have epidemiologic featuresin common.
Table 1. Clinical Characteristics of Long-Term Survivors.
Quantitation and Isolation of HIV-1
Infectious HIV-1 in plasma and peripheral-blood mononuclearcells (PBMC) was quantitated as described elsewhere.12,13,14Particle-associated RNA in plasma was quantitated with a modificationof the branched-DNA signal-amplification assay,15,16 with freshlycollected samples. This ultrasensitive assay has a typical detectionlimit of approximately 630 copies of RNA per milliliter of plasma.17HIV-1 DNA in PBMC was quantitated by the polymerase chain reaction(PCR) as described elsewhere.18 Briefly, proviral DNA was initiallystudied with limiting dilutions to a point at which less than25 percent of the resulting PCR products were positive. Thenumber of proviral copies was then estimated by the formula-ln(F), where F is the fraction of negative reactions, assumingthat the incidental appearance of positive PCR products followsa Poisson distribution. Appropriate positive and negative controlswere included in all quantitative assays.
When the initial attempt to isolate HIV-1 was unsuccessful,subsequent attempts were made with up to 5 million PBMC thathad been subjected to CD8+ lymphocyte depletion with immunomagneticbeads (Dynal, Great Neck, N.Y.).
Susceptibility of PBMC from Long-Term Survivors to HIV-1 Infection in Vitro
To assess the susceptibility of cells from long-term survivorsto HIV-1 infection in vitro, PBMC (2 million cells) from eachof eight study subjects (all except Subjects 1 and 9) and twonormal controls were inoculated with 3000 median tissue-cultureinfective doses (TCID50) of the HIV-1 isolate JRCSF.19 The cultureswere then washed extensively on the second day, and the expressionof p24 antigen in the supernatant was determined by an immunoassay(Abbott Laboratories, Abbott Park, Ill.) on days 4, 7, and 14of culture. Similar experiments were carried out in parallelwith PBMC that had been largely (>98 percent) depleted ofCD8+ lymphocytes by the immunomagnetic-bead method. In theseexperiments as well as those described immediately below, PBMCfrom subjects with progressive disease could not be studiedin parallel for comparison, because such cells harbor anotherinfectious isolate of HIV-1 that would have clouded the interpretationof the results.
HIV-1–Inhibitory Activity Mediated by CD8+ Lymphocytes
A series of experiments were conducted to quantitate the inhibitoryactivity of CD8+ lymphocytes on HIV-1 replication in CD4+ lymphocytes.CD4+ and CD8+ lymphocytes were each purified (to 98 percentpurity) from PBMC of long-term survivors and normal controlswith immunomagnetic beads. CD4+ lymphocytes were then stimulatedfor three days by the addition of phytohemagglutinin (2 µgper milliliter), and CD8+ lymphocytes were stimulated for threedays with an anti-CD3 monoclonal antibody (12F6), irradiatedallogeneic feeder cells, and interleukin-2 (100 units per milliliter).Two million CD4+ lymphoblasts were then inoculated with 3000TCID50 of the JRCSF isolate alone or together with variablenumbers of autologous activated CD8+ lymphocytes (from 1 milliondown to 320 in fivefold dilutions). The expression of p24 antigenin the culture supernatant was monitored periodically duringthe ensuing 14 days.
Neutralizing Activity of Plasma against Primary HIV-1 Isolates
Serial dilutions of plasma samples from nine long-term survivors(all subjects except Subject 1) and four subjects with progressivedisease were tested for neutralizing activity against a panelof 13 primary HIV-1 isolates (each containing 100 TCID50) obtainedafter short-term culture of PBMC from long-term survivors orfrom U.S. patients who had the acute infection syndrome, wereasymptomatic, or had AIDS. The assays were performed accordingto a published protocol,20,21 with 2 million activated PBMCfrom a normal donor used as target cells and the expressionof p24 antigen in the supernatant used as a measure of HIV-1replication. Extreme care was taken to ensure the complete removalof all added plasma from the cultures before the measurementof p24 antigen, because residual plasma might contain anti-p24antibodies capable of interfering substantially with the p24antigen assay, resulting in false evidence of virus neutralization.
Kinetics of Replication and Cytotoxicity of HIV-1 Isolates
HIV-1 was successfully isolated from the PBMC of three subjects(Subjects 8, 9, and 10) by a standard procedure,12,13,14 whereasin a fourth (Subject 7) isolation required CD8+ lymphocyte depletion.The kinetics of replication in 2 million PBMC from a normaldonor was determined for each viral isolate (3000 TCID50) byserial monitoring of p24 antigen expression in the culture supernatant,as described elsewhere. Viral cytotoxicity in purified culturesof CD4+ lymphocytes was assessed by serial counting of viablecells by light microscopy.14
Results
Levels of HIV-1 in PBMC and Plasma
The levels of HIV-1 in the PBMC and plasma of long-term survivorswere determined by several techniques. First, plasma cultureswere uniformly negative for infectious virus (<1 TCID50 permilliliter) in tests of nine subjects involving up to 1 ml ofsample (Figure 1). However, particle-associated HIV-1 RNA wasdetectable in four subjects (Subjects 4, 6, 8, and 10) by anultrasensitive branched-DNA assay15,16,17; the values rangedfrom 839 to 11,549 copies of RNA per milliliter of plasma. Theother five subjects had HIV-1 levels below the limit of detectionof the assay (<630 RNA copies per milliliter). Overall, theamount of HIV-1 in the plasma of these nine long-term survivorswas orders of magnitude lower than that found in subjects withprogressive disease. In our experience,12 asymptomatic personswith progressive disease had titers of infectious HIV-1 rangingfrom 5 to 100 TCID50 per milliliter of plasma (mean, 30), whereaspatients with AIDS had titers ranging from 5 to 5000 TCID50per milliliter (mean, about 1000). Similarly, subjects withprogressive disease in a recent study of ours had plasma countsof viral RNA ranging from 4000 to 90 million copies per milliliter.The mean values were 580,000 copies per milliliter among patientswith CD4+ cell counts below 200 per cubic millimeter and 71,000copies per milliliter among those with counts ranging from 200to 500 per cubic millimeter.16
Figure 1. Levels of HIV-1 in Plasma and PBMC of Long-Term Survivors.
Each symbol represents a study subject, identified in Table 1. TCID50 denotes median tissue-culture infective dose, and bDNA branched DNA. The detection limit of the bDNA signal-amplification assay was 630 copies of RNA per milliliter of plasma.
Levels of HIV-1 were also determined in the PBMC of long-termsurvivors. Infectious HIV-1 was detected and quantified in threesubjects (0.2, 50, and 5 TCID50 per million cells in Subjects8, 9, and 10, respectively) by a standard limiting-dilutionassay12,13,14 (Figure 1). In contrast, seven subjects had nodetectable infectious virus in 10 million PBMC (<0.1 TCID50per million cells). These negative results are particularlystriking because in other settings we have isolated HIV-1 fromPBMC at a rate approaching 100 percent.12,13,14 Therefore, additionalattempts to recover infectious HIV-1 were made with 2 millionto 5 million PBMC depleted of CD8+ lymphocytes, because thismaneuver has been shown to improve the efficiency of HIV-1 isolation.22,23,24,25The cultures for Subjects 1 through 6 remained negative, althoughan HIV-1 isolate was obtained from Subject 7 by this method(data not shown).
The amount of HIV-1 proviral DNA in the PBMC of long-term survivorswas determined by an established method of quantitative PCR.18As Figure 1 shows, all the subjects had detectable viral DNA,but the copy numbers were generally quite low, ranging from10 to 100 copies per million PBMC, except in Subjects 9 and10, who had 296 and 1783 copies per million PBMC, respectively.These two subjects also had the highest titers of infectiousHIV-1 in PBMC (Figure 1). Once again, the amount of HIV-1 inthe PBMC of long-term survivors as measured by these two techniquesappeared to be substantially lower than the levels that we12,13,14and others18,26,27,28 have found in patients with progressivedisease; such patients had a mean infectious titer of about1700 TCID50 per million PBMC and a mean count of about 5000copies of proviral DNA per milliliter.
It therefore appears that in the long-term survivors we studied,HIV-1 replication is well controlled in vivo. What accountsfor this finding? The experiments described below pursue threepossible explanations: that these patients' CD4+ lymphocytesare less susceptible to HIV-1 infection; that they have strongerHIV-1–specific immune responses; and that they harborstrains of HIV-1 that are defective or attenuated.
Susceptibility of PBMC from Long-Term Survivors to HIV-1 Infection in Vitro
PBMC from eight long-term survivors (all except Subjects 1 and9) and two normal controls were examined for their in vitrosusceptibility to infection by JRCSF,19 an exogenous strainof HIV-1, since no infectious virus was found in cells fromany of the subjects except Subjects 8 and 10. As Figure 2 shows,the virus replicated efficiently to high levels (>10,000pg of p24 antigen per milliliter) in the PBMC of two normaldonors, whereas its replication in the PBMC of long-term survivorswas substantially less. In fact, only one culture (of cellsfrom Subject 4) reached a level of p24 antigen expression >1000pg per milliliter. At first glance, these results suggest thatcells from long-term survivors were more refractory to HIV-1infection in vitro. However, when the cultures were depletedof CD8+ lymphocytes, the remaining CD4-enriched PBMC from eachlong-term survivor supported HIV-1 replication at levels inexcess of 1000 pg of p24 antigen per milliliter, and in fivesubjects the level exceeded 10,000 pg per milliliter (Figure 2).On average, CD8+ lymphocyte depletion produced a 22-foldincrease in peak HIV-1 replication in PBMC from the eight long-termsurvivors, as compared with a 3-fold increase in the two normalcontrols. Although CD4-enriched PBMC from several long-termsurvivors (for example, Subjects 6 and 8) w ere less efficientin replicating the JRCSF isolate (Figure 2), these cells didsupport the efficient growth of other primary HIV-1 isolates(data not shown). On the basis of the findings shown in Figure 2,we conclude that the CD4+ lymphocytes from long-term survivorshad no gross intrinsic resistance to HIV-1 infection in vitro.Instead, there is strong evidence to suggest that CD8+ lymphocytesfrom these survivors had substantial HIV-1–inhibitoryactivity.
Figure 2. Kinetics of Replication of HIV-1 Isolate JRCSF in PBMC and CD8-Depleted PBMC from Eight Long-Term Survivors and Two Normal Controls.
Each symbol represents a study subject identified in Table 1. Two normal donors are also shown ( and ).
Detection and Quantitation of HIV-1–Suppressive Activity of CD8+ Lymphocytes
To show conclusively that CD8+ lymphocytes from long-term survivorsindeed mediate potent suppression of HIV-1 replication in vitro,a series of experiments were performed in which CD8+ lymphocyteswere added back to the sample. The results of three such experimentsare shown in Figure 3. In CD4-enriched PBMC from a normal donor,the JRCSF strain of HIV-1 replicated efficiently to high levels,and the addition of 320 to 1 million autologous CD8+ lymphocytesresulted in only slight reductions in viral replication. Incontrast, for Subjects 2 and 5, the addition of autologous CD8+lymphocytes led to marked reductions (by about two orders ofmagnitude) in HIV-1 replication. In quantitative experimentsof this type, we were able to determine the minimal number ofautologous CD8+ lymphocytes required to inhibit peak HIV-1 replicationby 90 percent for eight long-term survivors, as follows: Subject2, 40,000 CD8+ lymphocytes; Subject 3, 200,000; Subject 4, 200,000;Subject 5, less than 300; Subject 6, 1 million; Subject 7, lessthan 40,000; Subject 8, 200,000; and Subject 10, 200,000. Thesefindings show that long-term survivors had a quantitativelygreater HIV-1–suppressive response to CD8+ lymphocytesthan did subjects with progressive disease, in whom 1 millionautologous CD8+ lymphocytes were generally required to inducesubstantial inhibition of viral replication.22,23,24
Figure 3. Kinetics of Replication of HIV-1 Isolate JRCSF in Unfractionated PBMC () from a Normal Control and Subjects 2 and 5, as Well as in CD8-Depleted, CD4-Enriched PBMC without CD8+ Lymphocytes (•) and with 1 Million (), 200,000 (), 40,000 (), 8000 (), 1600 (), and 320 () Autologous CD8+ Lymphocytes Added Back to the Cell Culture.
Neutralizing Activity of Plasma against HIV-1
Having detected evidence of a strong cellular immune response,we next turned our attention to the neutralizing activity ofplasma samples from nine long-term survivors against a diversepanel of primary HIV-1 isolates. The results are shown in Table 2.Although primary HIV-1 isolates are known to be relativelyresistant to neutralization by antibody and soluble CD4,21,29plasma samples from our long-term survivors had broad neutralizingactivity in general, especially when compared with the lackof neutralizing activity of plasma samples from subjects withprogressive disease. These findings suggest that the long-termsurvivors had vigorous functional antibody responses directedagainst HIV-1.
Table 2. Effectiveness of Plasma from Long-Term Survivors and Controls with Progressive Disease in Inhibiting Infection by Primary HIV-1 Isolates.
Characterization of the Biologic Properties of HIV-1 Isolates in Vitro
As has been mentioned, infectious HIV-1 could not be isolatedfrom six subjects despite multiple attempts using optimal protocols.Nevertheless, HIV-1 was recovered from PBMC of three subjects(Subjects 8, 9, and 10) by a standard method and from a fourth(Subject 7) by a CD8-depleted coculture. The kinetics of replicationin these four isolates was assessed in normal activated PBMC,as shown in Figure 4A. The isolates from Subjects 9 and 10 replicatedto levels similar to that of a wild-type isolate (JRCSF); incontrast, the isolates from Subjects 7 and 8 both replicatedto maximal levels of p24 antigen expression that were below1000 pg per milliliter, a finding consistent with substantialattenuation of growth. None of the four isolates were capableof infecting a number of T-cell lines, including MT-2 cells,and thus none were considered to have a syncytium-inducing phenotype.The cytotoxicity of these isolates against normal purified CD4+lymphocytes was also examined in vitro. As Figure 4B shows,the isolate from Subject 8 had no cytotoxic effect at all, whereasthose from Subjects 7, 9, and 10 were somewhat cytotoxic, thoughless so than JRCSF, which is generally not considered to beone of the more cytotoxic variants among well-characterizedHIV-1 isolates. On the basis of these findings, we believe thatviral attenuation was evident in Subjects 7 and 8.
Figure 4. Kinetics of Replication (Panel A) and Cytotoxic Effect on CD4+ Lymphocytes (Panel B) of HIV-1 Isolates from Long-Term Survivors and of the JRCSF Isolate ().
Each symbol represents a study subject, identified in Table 1. In panel B, denotes a control culture without virus.
Discussion
In the asymptomatic long-term survivors we have described, HIV-1replication appeared to be well controlled, with the viral loadin plasma and PBMC orders of magnitude lower than those typicallyfound in subjects with progressive disease (Figure 1). Recently,low levels of HIV-1 in lymphoid tissues of other long-term survivorshave also been reported.30 These findings are consistent withthose of a large number of published reports suggesting thatdisease progression is driven by an increasing viral burden.12,14,16,18,26,27,28,31,32,33
In eight of our long-term survivors (all except Subjects 9 and10) there were distinctive virologic features. Repeated attemptsto isolate infectious HIV-1 from six of the eight subjects wereunsuccessful (Figure 1); in the other two (Subjects 7 and 8),viral attenuation was evident (Figure 4A and Figure 4B). Thesefindings, coupled with the extremely low viral loads observed,suggest that these subjects may not merely represent one extremeend of the normal distribution of patients with HIV-1 infection.These eight subjects were phenotypically similar to the long-termsurvivor reported by Greenough et al.11 In contrast, Subjects9 and 10, who had higher viral burdens and wild-type–likeviruses, were more similar to the subjects with long-term nonprogressivedisease studied by Pantaleo et al.,30 who found higher viralburdens (mean plasma RNA copy number, 70,000 per milliliter)and obtained higher rates of virus isolation than those reportedhere. It is not clear that such subjects, although they meetthe current clinical definition of long-term survivors,6 willnot have progressive disease in the coming years.
We also studied three potential mechanisms that would accountfor the low viral load in long-term survivors: host-cell resistance,strong immunity, and weakened virus. Our study of the CD4+ lymphocytesin our subjects did find efficient replication of HIV-1 in vitroand the absence of gross intrinsic resistance to the virus.However, varying degrees of efficiency in viral replicationwere observed among the CD4+ lymphocytes from these subjects,as we34 and others35 have seen with cells from normal donors.
In a manner consistent with an earlier report showing that personswith long-term nonprogressive disease have higher levels ofHIV-1–specific antibodies and CD8+ lymphocytes,36 we foundevidence of vigorous immune responses to HIV-1. Figure 2 andFigure 3 show a substantial HIV-1–suppressive responseby CD8+ lymphocytes in all the subjects studied. This suppressiveeffect of CD8+ lymphocytes was not restricted to cells withHLA compatibility and was more efficient if there was cell-to-cellcontact (data not shown). Therefore, it is likely that theseCD8+ lymphocytes were qualitatively similar to those with thevirus-inhibitory characteristics described by Walker et al.22,23,24Although the nature of these inhibitory cells remains elusive,it is known that clones of cytotoxic T lymphocytes, when activatedin vitro, can mediate similar inhibition.37 Cytotoxic T lymphocytesthat recognize specific HIV-1 envelope, core, and polymeraseproducts have been detected in samples of PBMC from Subjects1 through 7 and 10 (unpublished data).
These long-term survivors also had potent and broad neutralizing-antibodyresponses against a diverse panel of primary HIV-1 isolates(Table 2). This was in distinct contrast to findings in subjectswith progressive disease29 (and Table 2). The presence of ahigh level of neutralizing-antibody activity and a vigorousCD8+ lymphocyte response indicates that the immune system ofthe long-term survivors must have been continually exposed toviral antigens.
We obtained mixed results with respect to HIV-1 attenuationin long-term survivors. Subjects 9 and 10 had higher viral loadsand harbored HIV-1 isolates that replicated as efficiently aswild-type viruses. In contrast, isolates from Subjects 7 and8 showed markedly reduced rates of replication in vitro. Wespeculate that the degree of viral attenuation may have beeneven higher in the subjects from whom we could not isolate thevirus. The viral genome of these long-term survivors is currentlybeing characterized in order to elucidate the possible geneticbasis of such attenuation. To date, no evidence of a gross nefdefect has been found in our 10 subjects,38 although one suchcase has been identified by others.39 Recently, defects in theNFB and Sp1 sites within the viral long-terminal repeats havebeen found in two of our subjects (unpublished data).
Two previous reports strongly support the notion that viralcharacteristics have a critical role in long-term nonprogressiveinfection. First, Learmont et al.10 described six recipientsof blood transfusions from one HIV-1–infected donor whohave remained well and immunologically stable despite a decadeof infection. The blood donor has also remained healthy. Thiscluster of long-term survivors suggests the possibility thatan attenuated virus was transmitted. Second, experiments carriedout by Kestler et al.40 showed that monkeys experimentally inoculatedwith simian immunodeficiency virus with deletions in the nefgene had no signs of disease and maintained low viral burdensalong with normal CD4+ T-cell counts. This study showed conclusivelythat viral attenuation can result in long-term nonprogressiveinfection.
In summary, the long-term survivors we studied had low levelsof HIV-1 in the presence of strong virus-specific immune responsescombined with some degree of viral attenuation, thereby tippingthe balance in favor of the infected host. The level of virusand the degree of immunity observed in these subjects couldserve as important guideposts for our therapeutic and prophylacticefforts against AIDS. Ideally, therapies should aim to reducethe burden of HIV-1 to the levels seen in long-term survivorsor below, and vaccines should attempt to induce the type ofimmunity found in these subjects. Most important, perhaps, long-termsurvivors of HIV-1 infection provide a ray of hope indicatingthat it is possible to live with the virus for prolonged periodswithout harm.
Supported by grants (AI24030, AI25541, AI32427, and AI27665)from the National Institutes of Health (NIH) and an NIH contracton Correlates of Immune Protection, the Centers for AIDS Researchof New York University, and the Aaron Diamond Foundation.
We are indebted to the study subjects for their participation,to R. Koup and J. Moore for helpful suggestions, and to W. Chenfor the preparation of the figures.
Source Information
From the Aaron Diamond AIDS Research Center, New York University School of Medicine, 455 First Ave., New York, NY 10016, where reprint requests should be addressed to Dr. Ho.
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B and Sp1 sites within the viral long-terminal repeats have been found in two of our subjects (unpublished data). 
), and TNF-
when they encounter their target antigens. J Virol 1993;67:2844-2852. 
and 
).
) from a Normal Control and Subjects 2 and 5, as Well as in CD8-Depleted, CD4-Enriched PBMC without CD8+ Lymphocytes (•) and with 1 Million (
), 200,000 (
), 40,000 (
), 8000 (
), 1600 (
), and 320 (
) Autologous CD8+ Lymphocytes Added Back to the Cell Culture.
