![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
Previous Article | Next Article 
Journal of Virology, February 2000, p. 2023-2028, Vol. 74, No. 4
Servicio de Medicina Interna 1, Clinica
Puerta de Hierro, Universidad Autonoma de Madrid, and Servicio de
Microbiologia, Hospital General Gregorio Maranon, Madrid,
Spain,1 and Laboratory of
Immunoregulation2 and Laboratory of Host
Defense,4 National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, and
SAIC/Frederick, Frederick Cancer Research and Development
Center, Frederick,3 Maryland
Received 11 February 1999/Accepted 10 November 1999
High levels of resistance to challenge with human immunodeficiency
virus type 1 SF162 were observed in animals engrafted with peripheral
blood mononuclear cells of four long-term nonprogressors (LTNPs).
Resistance was abrogated by depletion of CD8+ T cells in
vivo and was observed only in LTNPs with proliferative responses to
p24. In a subgroup of nonprogressors, CD8+ T cells mediated
restriction of challenge viruses, and this response was associated with
strong proliferative responses to p24 antigen.
Although patients with normal
CD4+ T-cell counts and low levels of virus in plasma are a
heterogeneous group, a small subgroup of patients with truly
nonprogressive human immunodeficiency virus (HIV) infection likely hold
important clues to the basis of an effective immune response to HIV. It
now appears clear that a large fraction of patients previously
considered long-term nonprogressors (LTNPs) ultimately show a decline
of CD4+-T-cell numbers. Members of a small subpopulation
(<0.8% of HIV-infected individuals) show no signs of progression over
a 10-year period (12, 22, 23, 36). Extensive studies have
demonstrated strong cellular and humoral HIV-directed responses in
LTNPs (2, 6, 7, 15, 18, 29, 31, 32). Regardless of the host or virus factors involved in nonprogression in these patients, a clear
demonstration of immunity-mediated resistance to challenge virus and
targets of such a response within HIV would enhance development of an
effective HIV vaccine. Recently we established a human HIV-peripheral
blood mononuclear cell (PBMC)-SCID mouse model, a modification of the
method developed by Mosier et al. (13, 26, 28), to study the
PBMC of infected patients (5). We determined whether PBMC of
LTNPs support replication of patients' autologous viruses in this
model and further whether these PBMC mediate restriction of
challenge-virus replication.
Engraftment of CB-17 SCID mice and sample collection were performed as
previously described (5). Animals were challenged intraperitoneally with HIVSF162 on day 7 and sacrificed on
day 21. To deplete CD8+ T cells, on day 6 animals received
0.2 mg of 7ptF9 anti-CD8 monoclonal or 833ICG isotype control antibody
(Coulter, Hialeah, Fla.). In preliminary experiments the 7ptF9 antibody
was not blocked by the detecting antibody to CD8. Because there is no
substantial lymphopoiesis, 7ptF9 treatment resulted in high-level
(>98%) depletion of CD8+ T cells throughout the
experimental period. Proviral DNA and plasma viral RNA assays were
performed using the Perkin-Elmer (Foster City, Calif.) model 7700 sequence detector. Dunnett's test for multiple comparisons was used to
compare the percentages of CD4+ T cells and the Wilcoxon
two-sample test was used with the Bonferroni multiple-testing
correction to compare levels of virus in plasma and provirus in spleen
between groups of animals. In vitro cultures were performed as
previously described (3). Standard enzyme-linked immunosorbent assays were used to quantify the CC chemokines MIP-1 All patients have been infected for greater than 13 years (Table
1). Two patients typically classified as
LTNPs (27, 35) were included as controls. These two patients
(patients 1 and 2) had levels of HIV RNA in plasma of <500 to 14,650 copies/mm3 at three or four time points over the past 4 years of study. Patients 3 to 6 consistently had plasma HIV RNA levels
of <50 copies/ml and no recovered virus in
CD8+-T-cell-depleted cocultures or in UV-irradiated
cultures (9).
0022-538X/00/$04.00+0
Resistance to Replication of Human Immunodeficiency
Virus Challenge in SCID-Hu Mice Engrafted with Peripheral Blood
Mononuclear Cells of Nonprogressors Is Mediated by CD8+
T Cells and Associated with a Proliferative Response to p24
Antigen
ABSTRACT
Top
Abstract
Text
References
TEXT
Top
Abstract
Text
References
, MIP-1
, and RANTES (R&D Systems, Minneapolis, Minn.) or p24
(Coulter). Standard 51Cr-release assays (37) and
proliferation assays (33) were performed as previously described.
TABLE 1.
Clinical data of study patientsa
In a previous study, engraftment of CB-17 SCID mice with PBMC from HIV-infected patients resulted in rapid replication of patient-derived (autologous) viruses (5). Plasma viremia peaked on day 10 and was associated with depletion of CD4+ T cells to 5% of human cells. This pattern was repeatedly observed in animals engrafted with PBMC of seven patients with progressive disease (not shown). However, in some experiments there was no replication of the patients' autologous viruses in animals engrafted with cells from two true LTNPs (patients 3 and 6). This observation permitted the study of restriction of challenge-virus replication in animals engrafted with PBMC of these patients. In preliminary experiments, upon challenge with 5 to 125 50% tissue culture infectious doses (TCID50) of HIVLAV, CD4+ T cells were maintained in animals engrafted with cells from patients 3 and 6 (not shown). We then determined if similar resistance would be observed upon challenge with the macrophage-tropic primary isolate HIVSF162. In animals engrafted with cells from an uninfected donor, significant depletion of CD4+ T cells (P = 0.05) and increases in levels of virus in plasma (P < 0.03) and of proviral DNA (P = 0.03) were observed at the 5- to 125-TCID50 doses when results were compared to results with unchallenged animals (Fig. 1). In both challenged and unchallenged animals engrafted with PBMC from patients 1 and 2, virus replication and CD4+-T-cell depletion were similar to those previously observed in animals engrafted with PBMC from progressors (5).
|
In contrast, animals engrafted with the cells from three of the four LTNPs (patients 4 to 6) did not replicate autologous viruses above levels of detection. Although unchallenged animals engrafted with cells from patient 3 had a lower percentage of CD4+ T cells than those of patients 4 to 6, no CD4+ T-cell depletion from this lower baseline was detected in challenged animals. No depletion of CD4+ T cells was observed in the majority of groups of animals engrafted with PBMC of patients 3 to 6 over a broad range of challenge doses when levels were compared to levels in unchallenged animals. Significant depletion of CD4+ T cells was found only in animals engrafted with the cells of patient 6 and challenged with 125 TCID50 (P = 0.05). No significant increase in virus in plasma was detected in challenged animals engrafted with PBMC of patients 3 to 6 when levels were compared with levels in unchallenged animals. Although several animals engrafted with the PBMC of patient 4 had plasma viremia, the distribution of these values was not significantly greater than that of unchallenged animals when values were corrected for multiple comparisons (P = 0.07). Significant increases in provirus in spleen were observed only in animals engrafted with PBMC of patient 4 and challenged with 125 TCID50 (P < 0.003). Sequence analysis of proviral DNA from the spleens of two of these animals confirmed that the virus detected was HIVSF162.
In separate experiments, the effect of CD8+-T-cell depletion on restriction of virus replication was investigated (Fig. 1). In animals engrafted with cells from patient 3 or 5 and depleted of CD8+ T cells, challenge virus replicated to levels comparable to those of animals engrafted with PBMC from an uninfected control. This replication resulted in significant increases in virus in plasma (P = 0.05) and provirus in spleen (P = 0.03) when such levels were compared to levels in 25-TCID50-challenged, nondepleted animals. Because CD8+-T-cell depletion increases the percentage of CD4+ T cells in the peritoneal wash, comparisons were made with similarly depleted, unchallenged animals. Increased virus replication in CD8+-T-cell-depleted animals resulted in only partial CD4+-T-cell depletion in those animals engrafted with the cells of patient 3 but significant depletion in the mice engrafted with cells from patient 5 (P < 0.03).
Because it is possible that restricted challenge-virus replication
might not be entirely due to a CD8+-T-cell response but
also to restriction of replication at the level of the CD4+
T cell, the ability to replicate virus in the absence of
CD8+ T cells was investigated in vitro. In cultures
depleted of CD8+ T cells (<1% residual CD8+ T
cells), no residual restriction of the replication of
HIVSF162 or HIVLAV was observed (not shown).
The lack of a deletion within the CCR5 gene was confirmed by
restriction fragment length polymorphism analysis. We also investigated
whether patients 3 to 6 could be distinguished from patients 1 and 2 in
standard assays of CD8+ T-cell-mediated HIV-specific
immunity. PBMC of patients 3 to 6 did not show a greater ability to
suppress replication of HIVSF162 or HIVLAV than
those of patients 1 and 2. Similar results were obtained with 5, 50, and 125 TCID50 of HIVSF162 or
HIVLAV or when CD8+ T cells were depleted and
then repleted at various ratios (100:0 to 100:100 CD4/CD8 ratios) (not
shown). No differences in the levels of the CC chemokines MIP-1,
MIP-1, and RANTES were found in the supernatants of cultures. No
difference in the magnitudes of the direct cytotoxic T lymphocyte (CTL)
responses was detected in patients 1 and 2 when their responses were
compared to those of patients 3 to 6. PBMC of uninfected patients and
patients with detectable virus in plasma (patients 1 and 2) showed no
proliferative response to p24 (Fig. 2).
In contrast, patients 3 to 6 had strong responses to p24 (stimulation
index, 10 to 140) that were abrogated by CD4+-T-cell
depletion in vitro.
|
The data from this study establish this resistance phenotype in a unique subgroup of nonprogressors that likely make up less than 0.8% of the HIV-infected population. These patients are characterized by nonprogressive disease, a level of virus in plasma below 50 copies/ml, a lack of readily detectable virus by culture, a lack of autologous virus replication in the SCID-Hu mouse, and strong proliferative responses to HIV antigens. Data from this study as well as previous epidemiologic data (12, 22, 23, 30, 33, 36) indicate that each of these characteristics is quite rare among patients with slowly progressive or nonprogressive disease, yet each of these was associated with the subgroup described here. Although the in vivo phenotype has been repeatedly observed over the past 4 years of study of these patients, no in vitro correlate which clearly distinguished patients 3 to 6 from progressors or other nonprogressors was found until the proliferative responses to HIV antigens in such patients and experimental animals was recently described (10, 11, 33).
It should be stressed that these data do not directly indicate the mechanism by which patients 3 to 6 have avoided progressive disease. The model presented is not a model of nonprogression; rather, it is a model of immunity-mediated restriction of a challenge virus. These data do extend some recent data documenting the role of CD8+ T cells in restricting virus replication in macaques chronically infected with simian/human immunodeficiency virus or simian immunodeficiency virus (16, 24, 34). It should also be noted that the SCID-Hu mouse model does not directly model all of the aspects of resistance to challenge observed in virus infection of a natural host. In the SCID-Hu mouse model, the lack of lymphopoiesis and moderate lymphocyte activation leads to rapid virus replication and CD4+-T-cell depletion. The lack of virus replication and CD4+-T-cell depletion in many animals engrafted with cells from patients 3 to 6 suggests that the form of resistance mediated by the CD8+ T cells of these patients is quite potent.
We did not detect higher levels of HIV-specific
CD8+-T-cell-mediated immunity by in vitro assays of PBMC
from patients 3 to 6 compared to those of patients 1 and 2. In the PBMC
of patients 1 and 2, who meet the widely used criteria of
nonprogressors (27, 35), high levels of suppressive and
direct CTL were observed, yet these responses were not associated with
restriction of autologous virus replication in the mouse model.
However, the CTL and CD8+-T-cell repletion assays used are
crude and nonquantitative and thus might have underestimated greater
HIV-specific CD8+-T-cell responses in patients 3 to 6. By a
more quantitative assay, the numbers of antigen-specific
CD8+ T cells detected by antigen-specific accumulation of
intracellular gamma interferon (IFN-
) of patients 3 to 6 were
similar to those of patients 1 and 2 and other patients with
progressive disease (J. Gea-Banacloche, unpublished data), consistent
with one other recent report (8). It should also be noted
that each of these assays measures responses to laboratory test strains
and might not measure dominant responses to the in vivo virus strain.
It is possible that the measured responses then underestimate the responses to the circulating viruses of patients 3 to 6. It is also
possible that maintenance of CD4+-T-cell help in patients 3 to 6 results in the maintenance of high-avidity, HIV-specific
CD8+ T cells, which is not adequately measured by these
assays (1, 4, 14, 17, 19-21, 25).
Further definition of the mechanisms of CD8+-T-cell-mediated restriction of virus replication in the patients described in this study is likely to hold important clues to the parameters that should be measured or mechanisms that might be exploited as part of prophylactic or therapeutic vaccines for HIV. If such mechanisms are determined in vitro, the model described here may allow a further demonstration of their relationship with restriction of challenge-virus replication.
| |
ACKNOWLEDGMENTS |
|---|
We thank Betsey Herpin, Stephanie Mizell, and Linda Ehler for arranging patient apheresis and handling of clinical samples. We especially thank the patients involved in this study for their time and dedication to its completion. The 7ptF9 antibody was kindly supplied by Gary Toedter of Coulter Corporation. HIV RNA standards (contributed by James Bremer and DAIDS, NIAID) and HIVSF162 challenge virus (contributed by Jay Levy) were provided by the NIH AIDS Research and Reference Reagent Program.
Juan C. Lopez Bernaldo de Quiros was partially supported by grant 97/5079 from the Fondo de Investigaciones Sanitarias, Madrid, Spain.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: National Institutes of Health, Building 10, Room 11B-09, 10 Center Dr., MSC 1876, Bethesda, MD 20892. Phone: (301) 496-8057. Fax: (301) 402-0070. E-mail: mconnors{at}atlas.niaid.nih.gov.
| |
REFERENCES |
|---|
|
Top
Abstract
Text
References
|
|---|
| 1. |
Alexander-Miller, M. A.,
G. R. Leggatt, and J. A. Berzofsky.
1996.
Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy.
Proc. Natl. Acad. Sci. USA
93:4102-4107 |
| 2. |
Barker, E.,
C. E. Mackewicz,
G. Reyes-Teran,
A. Sato,
S. A. Stranford,
S. H. Fujimura,
C. Christopherson,
S. Y. Chang, and J. A. Levy.
1998.
Virological and immunological features of long-term human immunodeficiency virus-infected individuals who have remained asymptomatic compared with those who have progressed to acquired immunodeficiency syndrome.
Blood
92:3105-3114 |
| 3. | Barker, T. D., D. Weissman, J. A. Daucher, K. M. Roche, and A. S. Fauci. 1996. Identification of multiple and distinct CD8+ T cell suppressor activities: dichotomy between infected and uninfected individuals, evolution with progression of disease, and sensitivity to gamma irradiation. J. Immunol. 156:4476-4483[Abstract]. |
| 4. |
Bennett, S. R.,
F. R. Carbone,
F. Karamalis,
J. F. Miller, and W. R. Heath.
1997.
Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help.
J. Exp. Med.
186:65-70 |
| 5. | Boyle, M. J., M. Connors, M. E. Flanigan, S. P. Geiger, H. Ford, Jr., M. Baseler, J. Adelsberger, R. T. Davey, Jr., and H. C. Lane. 1995. The human HIV/peripheral blood lymphocyte (PBL)-SCID mouse. A modified human PBL-SCID model for the study of HIV pathogenesis and therapy. J. Immunol. 154:6612-6623[Abstract]. |
| 6. |
Cao, Y.,
L. Qin,
L. Zhang,
J. Safrit, and D. D. Ho.
1995.
Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection.
N. Engl. J. Med.
332:201-208 |
| 7. | Cohen, O. J., A. Kinter, and A. S. Fauci. 1997. Host factors in the pathogenesis of HIV disease. Immunol. Rev. 159:31-48[CrossRef][Medline]. |
| 8. |
Dalod, M.,
M. Dupuis,
J.-C. Deschemin,
D. Sicard,
D. Salmon,
J.-F. Delfraissy,
A. Venet,
M. Sinet, and J.-G. Guillet.
1999.
Broad, intense anti-human immunodeficiency virus (HIV) ex vivo CD8+ responses in HIV type 1-infected patients: comparison with anti-Epstein-Barr virus responses and changes during antiretroviral therapy.
J. Virol.
73:7108-7116 |
| 9. |
Deacon, N. J.,
A. Tsykin,
A. Solomon,
K. Smith,
M. Ludford-Menting,
D. J. Hooker,
D. A. McPhee,
A. L. Greenway,
A. Ellett,
C. Chatfield, et al.
1995.
Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients.
Science
270:988-991 |
| 10. | Dittmer, U., T. Nisslein, W. Bodemer, H. Petry, U. Sauermann, C. Stahl-Hennig, and G. Hunsmann. 1995. Cellular immune response of rhesus monkeys infected with a partially attenuated nef deletion mutant of the simian immunodeficiency virus. Virology 212:392-397[CrossRef][Medline]. |
| 11. | Dittmer, U., M. Spring, H. Petry, T. Nisslein, P. Rieckmann, W. Luke, C. Stahl-Hennig, G. Hunsmann, and W. Bodemer. 1996. Cell-mediated immune response of macaques immunized with low doses of simian immunodeficiency virus (SIV). J. Biotechnol. 44:105-110[CrossRef][Medline]. |
| 12. | Ferbas, J., A. H. Kaplan, M. A. Hausner, L. E. Hultin, J. L. Matud, Z. Liu, D. L. Panicali, H. Nerng-Ho, R. Detels, and J. V. Giorgi. 1995. Virus burden in long-term survivors of human immunodeficiency virus (HIV) infection is a determinant of anti-HIV CD8+ lymphocyte activity. J. Infect. Dis. 172:329-339[Medline]. |
| 13. | Gulizia, R. J., R. G. Collman, J. A. Levy, D. Trono, and D. E. Mosier. 1997. Deletion of nef slows but does not prevent CD4-positive T-cell depletion in human immunodeficiency virus type 1-infected human-PBL-SCID mice. J. Virol. 71:4161-4164[Abstract]. |
| 14. | Han, W. R., P. L. Mottram, L. J. Purcell, R. J. Plenter, and I. F. C. McKenzie. 1995. Infiltrating cells in mouse cardiac allografts after anti-CD4 monoclonal antibody treatment. Transplant. Proc. 27:2163[Medline]. |
| 15. | Harrer, T., E. Harrer, S. A. Kalams, T. Elbeik, S. I. Staprans, M. B. Feinberg, Y. Cao, D. D. Ho, T. Yilma, A. M. Caliendo, R. P. Johnson, S. P. Buchbinder, and B. D. Walker. 1996. Strong cytotoxic T cell and weak neutralizing antibody responses in a subset of persons with stable nonprogressing HIV type 1 infection. AIDS Res. Hum. Retrovirus. 12:585-592[Medline]. |
| 16. |
Jin, X.,
D. E. Bauer,
S. E. Tuttleton,
S. Lewin,
A. Gettie,
J. Blanchard,
C. E. Irwin,
J. T. Safrit,
J. Mittler,
L. Weinberger,
L. G. Kostrikis,
L. Zhang,
A. S. Perelson, and D. D. Ho.
1999.
Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques.
J. Exp. Med.
189:991-998 |
| 17. | Karupiah, G., R. M. Buller, N. Van Rooijen, C. J. Duarte, and J. Chen. 1996. Different roles for CD4+ and CD8+ T lymphocytes and macrophage subsets in the control of a generalized virus infection. J. Virol. 70:8301-8309[Abstract]. |
| 18. |
Klein, M. R.,
C. A. van Baalen,
A. M. Holwerda,
S. R. Kerkhof Garde,
R. J. Bende,
I. P. Keet,
J. K. Eeftinck-Schattenkerk,
A. D. Osterhaus,
H. Schuitemaker, and F. Miedema.
1995.
Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics.
J. Exp. Med.
181:1365-1372 |
| 19. |
Krieger, N. R.,
D. P. Yin, and C. G. Fathman.
1996.
CD4+ but not CD8+ cells are essential for allorejection.
J. Exp. Med.
184:2013-2018 |
| 20. |
Kurts, C.,
F. R. Carbone,
M. Barnden,
E. Blanas,
J. Allison,
W. R. Heath, and J. F. Miller.
1997.
CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity.
J. Exp. Med.
186:2057-2062 |
| 21. | Lee, P. P., C. Yee, P. A. Savage, L. Fong, D. Brockstedt, J. S. Weber, D. Johnson, S. Swetter, J. Thompson, P. D. Greenberg, M. Roederer, and M. M. Davis. 1999. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat. Med. 5:677-685[CrossRef][Medline]. |
| 22. | Lefrere, J. J., M. Mariotti, L. Morand-Joubert, M. Thauvin, and F. Roudot-Thoraval. 1999. Plasma human immunodeficiency virus RNA below 40 copies/mL is rare in untreated persons even in the first years of infection. J. Infect. Dis. 180:526-529[CrossRef][Medline]. |
| 23. |
Lefrere, J. J.,
L. Morand-Joubert,
M. Mariotti,
H. Bludau,
B. Burghoffer,
J. C. Petit, and F. Roudot-Thoraval.
1997.
Even individuals considered as long-term nonprogressors show biological signs of progression after 10 years of human immunodeficiency virus infection.
Blood
90:1133-1140 |
| 24. |
Matano, T.,
R. Shibata,
C. Siemon,
M. Connors,
H. C. Lane, and M. A. Martin.
1998.
Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques.
J. Virol.
72:164-169 |
| 25. |
Matloubian, M.,
R. J. Concepcion, and R. Ahmed.
1994.
CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection.
J. Virol.
68:8056-8063 |
| 26. |
Mosier, D. E.,
R. J. Gulizia,
S. M. Baird,
D. B. Wilson,
D. H. Spector, and S. A. Spector.
1991.
Human immunodeficiency virus infection of human-PBL-SCID mice.
Science
251:791-794 |
| 27. |
Pantaleo, G.,
S. Menzo,
M. Vaccarezza,
C. Graziosi,
O. J. Cohen,
J. F. Demarest,
D. Montefiori,
J. M. Orenstein,
C. Fox,
L. J. Schrager,
J. B. Margolick,
S. Buchbinder,
J. V. Giorgi, and A. S. Fauci.
1995.
Studies in subjects with long-term nonprogressive human immunodeficiency virus infection.
N. Engl. J. Med.
332:209-216 |
| 28. | Picchio, G. R., R. J. Gulizia, and D. E. Mosier. 1997. Chemokine receptor CCR5 genotype influences the kinetics of human immunodeficiency virus type 1 infection in human PBL-SCID mice. J. Virol. 71:7124-7127[Abstract]. |
| 29. | Pilgrim, A. K., G. Pantaleo, O. J. Cohen, L. M. Fink, J. Y. Zhou, J. T. Zhou, D. P. Bolognesi, A. S. Fauci, and D. C. Montefiori. 1997. Neutralizing antibody responses to human immunodeficiency virus type 1 in primary infection and long-term-nonprogressive infection. J. Infect. Dis. 176:924-932[Medline]. |
| 30. | Pontesilli, O., P. Carotenuto, S. R. Kerkhof-Garde, M. T. Roos, I. P. Keet, R. A. Coutinho, J. Goudsmit, and F. Miedema. 1999. Lymphoproliferative response to HIV type 1 p24 in long-term survivors of HIV type 1 infection is predictive of persistent AIDS-free infection. AIDS Res. Hum. Retrovirus. 15:973-981[CrossRef][Medline]. |
| 31. | Rinaldo, C., P. Piazza, Y. Z. Wang, J. Armstrong, P. Gupta, M. Ho, S. Petteway, D. Reed, D. Lyter, and L. Kingsley. 1988. HIV-1-specific production of IFN-gamma and modulation by recombinant IL-2 during early HIV-1 infection. J. Immunol. 140:3389-3393[Abstract]. |
| 32. | Rinaldo, C. R., Jr., L. A. Beltz, X. L. Huang, P. Gupta, Z. Fan, and D. J. Torpey, III. 1995. Anti-HIV type 1 cytotoxic T lymphocyte effector activity and disease progression in the first 8 years of HIV type 1 infection of homosexual men. AIDS Res. Hum. Retrovirus. 11:481-489[Medline]. |
| 33. |
Rosenberg, E. S.,
J. M. Billingsley,
A. M. Caliendo,
S. L. Boswell,
P. E. Sax,
S. A. Kalams, and B. D. Walker.
1997.
Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.
Science
278:1447-1450 |
| 34. |
Schmitz, J. E.,
M. J. Kuroda,
S. Santra,
V. G. Sasseville,
M. A. Simon,
M. A. Lifton,
P. Racz,
K. Tenner-Racz,
M. Dalesandro,
B. J. Scallon,
J. Ghrayeb,
M. A. Forman,
D. C. Montefiori,
E. P. Rieber,
N. L. Letvin, and K. A. Reimann.
1999.
Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.
Science
283:857-860 |
| 35. | Strathdee, S. A., P. J. Veugelers, K. A. Page-Shafer, A. McNulty, A. R. Moss, M. T. Schechter, G. J. van Griensven, and R. A. Coutinho. 1996. Lack of consistency between five definitions of nonprogression in cohorts of HIV-infected seroconverters. AIDS 10:959-965[Medline]. |
| 36. | Vesanen, M., C. E. Stevens, P. E. Taylor, P. Rubinstein, and K. Saksela. 1996. Stability in controlling viral replication identifies long-term nonprogressors as a distinct subgroup among human immunodeficiency virus type 1-infected persons. J. Virol. 70:9035-9040[Abstract]. |
| 37. | Walker, B. D. 1990. Techniques in HIV research. Stockton Press, New York, N.Y. |
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| J. Bacteriol. | Mol. Cell. Biol. | Microbiol. Mol. Biol. Rev. |
|---|
| Clin. Vaccine Immunol. | ALL ASM JOURNALS |
|---|
