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PubMed1991

Importance of purine and pyrimidine content of local nucleotide sequences (six bases long) for evolution of the human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 evolves rapidly, and random base change is thought to act as a major factor in this evolution. However, segments of the viral genome differ in their variability: there is the highly variable env gene, particularly hypervariable regions located within env, and, in contrast, the conservative gag and pol genes. Computer analysis of the nucleotide sequences of human immunodeficiency virus type 1 isolates reveals that base substitution in this virus is nonrandom and affected by local nucleotide sequences. Certain local sequences 6 base pairs long are excessively frequent in the hypervariable regions. These sequences exhibit base-substitution hotspots at specific positions in their 6 bases. The hotspots tend to be nonsilent letters of codons in the hypervariable regions--thus leading to marked amino acid substitutions there. Conversely, in the conservative gag and pol genes the hotspots tend to be silent letters because of a difference in codon frame from the hypervariable regions. Furthermore, base substitutions in the local sequences that frequently appear in the conservative genes occurred at a low level, even within the variable env. Thus, despite the high variability of this virus, the conservative genes and their products could be conserved. These may be some of the strategies evolved in human immunodeficiency virus type 1 to allow for positive-selection pressures, such as the host immune system, and negative-selection pressures on the conservative gene products.

Acquired Immunodeficiency Syndrome↗

PubMed1997

A natural polymorphism in beta-lactamase is a global suppressor.

A M182T substitution was discovered as a second-site suppressor of a missense mutation in TEM-1 beta-lactamase. The combination of the M182T substitution with other substitutions in the enzyme indicates the M182T substitution is a global suppressor of missense mutations in beta-lactamase. The M182T substitution also is found in natural variants of TEM-1 beta-lactamase with altered substrate specificity that have evolved in response to antibiotic therapy. The M182T substitution may have been selected in natural isolates as a suppressor of folding or stability defects resulting from mutations associated with drug resistance. This pathway of protein evolution may occur in other targets of antimicrobial drugs such as the HIV protease.

Enzyme Stability↗

PubMed2005

Not so different after all: a comparison of methods for detecting amino acid sites under selection.

We consider three approaches for estimating the rates of nonsynonymous and synonymous changes at each site in a sequence alignment in order to identify sites under positive or negative selection: (1) a suite of fast likelihood-based "counting methods" that employ either a single most likely ancestral reconstruction, weighting across all possible ancestral reconstructions, or sampling from ancestral reconstructions; (2) a random effects likelihood (REL) approach, which models variation in nonsynonymous and synonymous rates across sites according to a predefined distribution, with the selection pressure at an individual site inferred using an empirical Bayes approach; and (3) a fixed effects likelihood (FEL) method that directly estimates nonsynonymous and synonymous substitution rates at each site. All three methods incorporate flexible models of nucleotide substitution bias and variation in both nonsynonymous and synonymous substitution rates across sites, facilitating the comparison between the methods. We demonstrate that the results obtained using these approaches show broad agreement in levels of Type I and Type II error and in estimates of substitution rates. Counting methods are well suited for large alignments, for which there is high power to detect positive and negative selection, but appear to underestimate the substitution rate. A REL approach, which is more computationally intensive than counting methods, has higher power than counting methods to detect selection in data sets of intermediate size but may suffer from higher rates of false positives for small data sets. A FEL approach appears to capture the pattern of rate variation better than counting methods or random effects models, does not suffer from as many false positives as random effects models for data sets comprising few sequences, and can be efficiently parallelized. Our results suggest that previously reported differences between results obtained by counting methods and random effects models arise due to a combination of the conservative nature of counting-based methods, the failure of current random effects models to allow for variation in synonymous substitution rates, and the naive application of random effects models to extremely sparse data sets. We demonstrate our methods on sequence data from the human immunodeficiency virus type 1 env and pol genes and simulated alignments.

Amino Acids↗

PubMed2003

Bootstrap choice of estimators in parametric and semiparametric families: an extension of EIC.

Ishiguro, Sakamoto, and Kitagawa (1997, Annals of the Institute of Statistical Mathematics 49, 411-434) proposed EIC as an extension of Akaike criterion (AIC); the idea leading to EIC is to correct the bias of the log-likelihood, considered as an estimator of the Kullback-Leibler information, using bootstrap. We develop this criterion for its use in multivariate semiparametric situations, and argue that it can be used for choosing among parametric and semiparametric estimators. A simulation study based on aregression model shows that EIC is better than its competitors although likelihood cross-validation performs nearly as well except for small sample size. Its use is illustrated by estimating the mean evolution of viral RNA levels in a group of infants infected by HIV.

Age Factors↗

PubMed2004

Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis.

Most drugs used for prevention and treatment of Pneumocystis jirovecii pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of P. jirovecii drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in P. jirovecii DHFR from 33 patients diagnosed with P. jirovecii pneumonia who were receiving prophylaxis with a DHFR inhibitor (n = 15), prophylaxis without a DHFR inhibitor (n = 11), or no prophylaxis (n = 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18; P = 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that P. jirovecii populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to P. jirovecii drug resistance.

Adult↗

PubMed1999

Evolution and clonal traits of Mycobacterium tuberculosis complex in Guinea-Bissau.

Two hundred twenty-nine consecutive isolates of Mycobacterium tuberculosis complex from patients with pulmonary tuberculosis in Guinea-Bissau, which is located in West Africa, were analyzed for clonal origin by biochemical typing and DNA fingerprinting. By using four biochemical tests (resistance to thiophene-2-carboxylic acid hydrazide, niacin production, nitrate reductase test, and pyrazinamidase test), the isolates could be assigned to five different biovars. The characteristics of four strains conformed fully with the biochemical criteria for M. bovis, while those of 85 isolates agreed with the biochemical criteria for M. tuberculosis. The remaining 140 isolates could be allocated into one of three biovars (biovars 2 to 4) representing a spectrum between the classical bovine (biovar 1) and human (biovar 5) tubercle bacilli. By using two genotyping methods, restriction fragment length polymorphism analysis with IS6110 (IS6110 RFLP analysis) and spoligotyping, the isolates could be separated into three groups (groups A to C) of the M. tuberculosis complex. Group A (n = 95), which contained the majority of classical human M. tuberculosis isolates, had large numbers of copies of IS6110 elements (mean number of copies, 9) and a distinctive spoligotyping pattern that lacked spacers 33 to 36. Isolates of the major group, group B (n = 119), had fewer IS6110 copies (mean copy number, 5) and a spoligotyping pattern that lacked spacers 7 to 9 and 39 and mainly comprised isolates of biovars 1 to 4. Group C isolates (n = 15) had one to three IS6110 copies, had a spoligotyping pattern that lacked spacers 29 to 34, and represented biovar 3 to 5 isolates. Four isolates whose biochemical characteristics conformed with those of M. bovis clustered with the group B isolates and had spoligotype patterns that differed from those previously reported for M. bovis, in that they possessed spacers 40 to 43. Interestingly, isolates of group B and, to a certain extent, also isolates of group C showed a high degree of variability in biochemical traits, despite genotypic identity in terms of IS6110 RFLP and spoligotype patterns. We hypothesize that isolates of groups B and C have their evolutionary origin in West Africa, while group A isolates are of European descent.

Adult↗

PubMed1992

Evolution of the V3 envelope domain in proviral sequences and isolates of human immunodeficiency virus type 1 during transition of the viral biological phenotype.

The third variable domain (V3) of the envelope gene of human immunodeficiency virus type 1 contains a major neutralization epitope and determinants of syncytium-inducing (SI) capacity and replication rate (reviewed by J. P. Moore and P. L. Nara, AIDS Suppl. 2:S21-S33, 1991). Sequences were generated from DNA of samples taken 3 months apart over a period of 24 and 30 months from peripheral blood mononuclear cells (PBMC) of two individuals, both before and after cocultivation with uninfected donor PBMC. The isolated virus shifted from the non-syncytium-inducing (NSI) phenotype to the SI phenotype during the study period. This shift was associated with distinct changes in the V3 domain in both patients. The association of the phenotype shift with the V3 sequence changes was confirmed by construction of viruses with chimeric V3 loops. The shift from NSI- to SI-associated V3 variants was also seen in the uncultured PBMC of both patients, but not until 3 and 9 months after the detection of SI virus in culture. In the samples of uncultured PBMC DNA, several subgroups of sequences were found, indicating that the process of evolution may not be gradual and that several distinct populations can coexist. The paucity of intermediate sequences indicated that strong selection pressure was exerted on this part of the envelope. The early emergence of disease-associated SI variants in cultured material indicates that virus culture may have relevance for the in vivo situation.

Amino Acid Sequence↗

PubMed2005

Evolution of human immunodeficiency virus type 1 protease genotypes and phenotypes in vivo under selective pressure of the protease inhibitor ritonavir.

We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.

Acquired Immunodeficiency Syndrome↗

PubMed2002

[Chemokines and immunomodulation: applications for HIV infections].

The genetic control of HIV infection by the host involves a certain number of genes, among which those which code for chemokines/chemokines receptors, cytokines, MHC. Genes such as CCR5, CCR2, SDF1, and more recently CX3CR1 received great attention from several laboratories including ours, since they play a role as HIV coreceptor and, as such, on the infectivity of the host. In addition, it was shown that the polymorphism of these genes influences the evolution of infection, whether they have a protective or deleterious effect. Results obtained by our laboratory on the genetic polymorphism and its implication in HIV infection will be reported herein. Furthermore, to better understand their role, we looked for the capacities that the chemokines may have to play an immunomodulatory function, independently of their chemoattractive effect. In two examples, we showed that chemokines influence notably the cellular immune functions, such as CD8 cytotoxicity (Rantes/CCR3) and gamma interferon production (fractalkine/CX3CR1). Globally, the results indicate that chemokines/chemokines receptors polymorphism represent important epidemiological factors, but also contributes to evaluate the prognosis of HIV infection, through a better understanding of the disease physiopathology.

Chemokines↗

PubMedDate not supplied

[Acquired immunodeficiency syndrome-related lymphoma: 1. Course during the 20 years of the epidemic. 2. The experience at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán: 1986-2003].

The goal of this presentation is the description of the epidemiologic evolution and changes in natural history of the human immunodeficiency virus infection (HIV) epidemic itself and its relation with the acquired immunodeficiency syndrome-related lymphoma (ARL). We have started with the description of the world's state of the HIV epidemic, its features since the first case report in the United States of America in 1981, through the peak of new diagnoses in 1993 until the event that changed the natural history of the disease: the era of the widespread use of the highly active antiretroviral therapy (HAART), introduced in 1995 in the world and in 1997 in our country. The widespread introduction of HAART led to dramatic reductions in AIDS related mortality and morbidity throughout the developed world with a marked fall in the incidence of the major opportunistic infections in AIDS. We describe the main risk factors for the development of ARL, and the prognostic factors for survival and response to treatment. There is no clear definition in the literature of the roll that has played the use of HAART in relation to survival and response to treatment in ARL, but there is evidence that the basal count of CD4 cells has increased with HAART, leading to a better survival and response in ARL. The debate regarding this issue is surely affected by factors such as degree of antiretroviral treatment compliance, antiretroviral therapy resistance and chemotherapy heterogeneity. Finally we present the preliminary results of the analysis of our experience in ARL from 1986 to 2003.

Adult↗

PubMed2006

[Secondary amyloidosis with irreversible acute renal failure caused by visceral leishmaniasis in a patient with AIDS].

We report a case of visceral leishmaniasis and acute renal failure in a white male patient, 28 years of age, infected with the human immunodeficiency virus (HIV). The clinical presentation of the patient was diarrheic syndrome of long evolution, fever, hepatosplenomegaly and pancytopenia, accompanied by nephrotic syndrome and irreversible acute renal failure. Renal biopsy showed glomerular AA amyloid deposits. This is the first case described in humans of secondary amyloidosis caused by visceral leishmaniasis.

AIDS-Related Opportunistic Infections↗

PubMed1995

[Intestinal microsporidiosis in patients with AIDS: study of 3 cases].

Enterocytozoon bieneusi is a protozoa belonging to the Microsporidia family which prevalence has increased in AIDS patients. Although diagnosis is performed by the demonstration of the parasite in the epithelium of the small intestine by light and electron microscopy, techniques allowing diagnosis from stools or duodenal or biliary aspirates have recently been described. Three cases of intestinal microsporidiosis diagnosed by the mentioned method are reported. The patients were 3 males with chronic diarrhea of several months of evolution with an important ponderal loss. All were in advanced stages of HIV infection with CD4-lymphocyte counts lower than 0.1 x 10(9)/l. In all the patients in whom intestinal absorption tests were performed these were found to be altered. One of the patients presented concommitant cholestasis with parasitation by E. bieneusi being demonstrated as by the biliary route in this patient. Confirmation of infection by E. bieneusi was performed in the 3 cases by electron microscopy study of stools. A review of intestinal microsporidiosis in AIDS patients is carried out and the therapeutic possibilities available for this infection are discussed.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Evolution of coreceptor use and CD4-independence in envelope clones derived from SIVsm-infected macaques.

Coreceptor use of HIV can evolve during infection. We previously examined coreceptor use of related SIVsm inoculum viruses and sequential reisolates from cynomolgus macaques. These viruses exhibited broad coreceptor specificities and, generally, CCR5 use remained efficient and stable, while alternative coreceptor use decreased longitudinally. Here we demonstrate that individual envelopes (Envs) from inoculum and reisolate viruses fuse via a range of coreceptors, including CCR5, CCR8, CXCR6, GPR15, GPR1, and APJ. On the whole, coreceptor use of Envs from sequential reisolates recapitulated that of reisolate viruses, thus CCR5 use remained stable while alternative coreceptor use tended to decrease over time. Rhesus CCR5, GPR15, and CXCR6 supported fusion to a similar extent as their human counterparts. Additionally, a number of Envs mediated CD4-independent fusion via CCR5 and GPR15. Envs from different inoculum viruses exhibited distinct dependencies on CD4 for fusion via CCR5, ranging from strictly CD4-dependent to efficiently CD4-independent. Early reisolates from macaques infected with CD4-independent inoculums maintained or evolved Envs with a broad range of CD4-independence. CD4-independence became less variable/efficient in late reisolates from macaques that developed neutralizing antibodies. Infection with a CD4-dependent virus resulted in evolution of CD4-independent Envs in late reisolates. While CD4 independence can potentially broaden tropism in vivo, CD4-independent viruses are particularly sensitive to neutralizing antibodies. Therefore, interplay between receptor tropism and neutralization may shape viral evolution and SIV pathogenesis.

Animals↗

PubMed2001

Molecular and phenotypic characteristics of neurotropic HIV-1 subtype E.

Although HIV-1 subtype E associated with neurological dysfunction is common, the virological characteristics of HIV-1 isolated from the CNS for this subtype have not yet been identified. In this study, paired blood and CSF isolated from patients with AIDs-defining illnesses were cultured, sequenced and aligned. Phylogenetic tree and nucleotide-distances from both blood and CSF were investigated. Cytopathicity and co-receptor usage of paired blood and CSF isolates were compared to define the specific characteristics of CNS isolates. The results confirmed that CSF isolates showed less cytopathicity. It was found that both blood and CSF isolates used either CXCR4 or CXCR4 and CCR5 as co-receptors. Interestingly, one CSF isolate using CCR3 as a co-receptor was identified. By sequence analysis, the pair-wise distances of envelope gp 120 sequence and those of all variable regions (except V3 region) between blood and CSF isolates were significantly different. The genetic distances in V1/V2 regions of CSF isolates showed more diversity than those of blood isolates. These findings suggest that the evolution of V1/V2 regions of CSF isolates seems to be an advantage for HIV-1 in CNS infection. In contrast, the genetic distance in V4 and V5 regions of CSF isolates showed less diversity, suggesting that conservation in these regions might be necessary during the process of HIV-1 CNS infection.

AIDS-Related Opportunistic Infections↗

PubMed2006

Analysis of the near full length genomes of HIV-1 subtypes B, F and BF recombinant from a cohort of 14 patients in São Paulo, Brazil.

The human immune deficiency virus (HIV) exhibits strikingly tremendous amount of genetic variability. Such feature is critically important for the virus to adapt to environmental changes by escaping the host immune system and by escaping candidate vaccine. Therefore, understanding of such diversity is fundamental for the design of successful drugs or vaccine, which is urgently needed to bring the HIV/AIDS epidemic under control. In this study, we investigated the magnitude of diversity of the HIV-1 near full-length genomes from patients previously assigned as infected with non-recombinant HIV-1 subtypes B and F1 variants based on small portion of viral genome. HIV-1 proviral DNA was extracted from 14 samples previously classified in our laboratory as six subtypes B and eight subtypes F on the basis of small amplicon sequencing. Reamplifications of DNA from these samples were carried out by an overlapping PCR followed by direct sequencing. The data were phylogenetically inferred. Sequence analysis revealed that two out of six partially identified subtype B and six out of eight partially identified subtype F were in fact BF recombinants throughout their full genomes. Two pairs BF recombinants had identical genomic recombination structure and distinct from the Argentinean CRF 12_BF strains, probably represents a novel circulating recombinant forms in Brazil. Our data provided new genetic material of some of the HIV-1 subtypes currently circulating in the country and points to the widespread of BF recombinants which are expected to change the epidemic nature by approaching the level of subtype B in Brazil.

Adult↗

PubMed2006

Viral evolution in macaques coinfected with CCR5- and CXCR4-tropic SHIVs in the presence or absence of vaccine-elicited anti-CCR5 SHIV neutralizing antibodies.

Macaques were immunized with SF162 Env-based gp140 immunogens and challenged simultaneously with the CCR5-tropic homologous SHIV(SF162P4) and the CXCR4-tropic heterologous SHIV(SF33A) viruses. Both mock-immunized and immunized animals became dually infected. Prior immunization preferentially reduced the viral replication of the homologous virus during primary infection but the relative replication of the two coinfecting viruses during chronic infection was unaffected by prior immunization, despite the fact that five of six immunized animals maintained a significantly lower overall viral replication that the control animals. Neutralizing antibodies participated in controlling the replication of SHIV(SF162P4), but not that of SHIV(SF33A). Dual infection resulted in the emergence and predominance within the circulating CCR5 virus pool, of a variant with a distinct neutralization phenotype. The signature of this variant was the presence of three amino acid changes in gp120, two of which were located in the receptor and coreceptor binding sites. Also, a significant fraction of the viruses circulating in the blood, as early as two weeks post-infection, was recombinants and prior immunization did not prevent their emergence. These findings provide new insights into the dynamic interaction of CCR5- and CXCR4-tropic HIV isolates that are potentially relevant in better understanding HIV-mediated pathogenesis.

AIDS Vaccines↗

PubMed1998

[Aids in Madagascar. II. Intervention policy for maintaining low HIV infection prevalence].

The HIV seroprevalence per 100,000 adults Malagasy rose from 20 in 1989, to 30 in 1992, and to 70 in 1995. In that year, the total number of HIV infected people in the Big Island was estimated at 5,000, the number of people sick with AIDS at 130, and the people at risk at more than 1,000,000. The latter are the persons infected with other STDs and individuals (or their partners) with risky sexual behaviour (e.g. numerous sexual partners, occasional sexual partners, and/or sexual contacts with commercial sex workers). The HIV prevalence rate is low as compared with those of other countries. Nevertheless, the spread of the HIV infection is alarming in some parts of the country and the risk factors are also present, namely: the high prevalence of STDs, numerous sexual partners, the low use of condoms in all groups, the development of tourism, the development of prostitution associated with social and economical problems, and internal and international migrations (with risky sexual contacts). Therefore, the still low but rising HIV prevalence in 1995 does not warrant complacency. To estimate the trend of HIV prevalence within the population, it is useful to know two different assumptions, as follows: firstly, a controlled evolution of the epidemic (low epidemic) and secondly, a very fast spread of the epidemic (high epidemic). If we consider the 5,000 individuals seropositive in July 1995, the Aids Impact Model (AIM) projection model shows that HIV seroprevalence rates among adults in 2015 might be between 3% (when the progression course of HIV epidemic is low) and 15% (when the progression course of HIV epidemic is high). By 2015 AIDS could have severe demographic, social, and economic impacts. Then, it is necessary to take measures to prevent contamination. Five major interventions are required: public information about AIDS, HIV transmission mechanism, and its prevention, communities education via the respected people and the notabilities to promote moral values, reduce the number of sexual partners, delay visit of sexual activity, and advice for infected couples; screening of blood donors and the supposed high risk group; control of STDs; reduction of the number of sexual partners; promotion of condom use, abstinence, and fidelity. To sum up, the fight against AIDS is not only the health professional workers' problem. It concerns all Malagasy people. Therefore, successfullness in prevention efforts to slow the epidemic needs concerted, collective, and long lasting actions from all sectors of the society for the nation's future and the well-being of the rising generations.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Vaccine protection against functional CTL abnormalities in simian human immunodeficiency virus-infected rhesus monkeys.

Accumulating evidence suggests that HIV-specific CD8(+) CTL are dysfunctional in HIV-infected individuals with progressive clinical disease. In the present studies, cytokine production by virus-specific CTL was assessed in the rhesus monkey model for AIDS to determine its contribution to the functional impairment of CTL. CTL from monkeys infected with nonpathogenic isolates of simian and simian-human immunodeficiency virus expressed high levels of IFN-gamma, TNF-alpha, and IL-2 after in vitro exposure to a nonspecific mitogen or the optimal peptide representing a dominant virus-specific CTL epitope. However, similarly performed studies assessing these capabilities in CTL from monkeys infected with pathogenic immunodeficiency virus isolates demonstrated a significant dysfunction in the ability of the CTL to produce IL-2 and TNF-alpha. Importantly, CTL from vaccinated monkeys that effectively controlled the replication of a highly pathogenic simian-human immunodeficiency virus isolate following challenge demonstrated a preserved capacity to produce these cytokines. These experiments suggest that defects in cytokine production may contribute to CTL dysfunction in chronic HIV or SIV infection. Moreover, an AIDS vaccine that confers protection against clinical disease evolution in this experimental model also preserves the functional capacity of these CTL to produce both IL-2 and TNF-alpha.

Animals↗