Neutralizing antibody responses in acute human immunodeficiency virus type 1 subtype C infection.

The study of the evolution and specificities of neutralizing antibodies during the course of human immunodeficiency virus type 1 (HIV-1) infection may be important in the discovery of possible targets for vaccine design. In this study, we assessed the autologous and heterologous neutralization responses of 14 HIV-1 subtype C-infected individuals, using envelope clones obtained within the first 2 months postinfection. Our data show that potent but relatively strain-specific neutralizing antibodies develop within 3 to 12 months of HIV-1 infection. The magnitude of this response was associated with shorter V1-to-V5 envelope lengths and fewer glycosylation sites, particularly in the V1-V2 region. Anti-MPER antibodies were detected in 4 of 14 individuals within a year of infection, while antibodies to CD4-induced (CD4i) epitopes developed to high titers in 12 participants, in most cases before the development of autologous neutralizing antibodies. However, neither anti-MPER nor anti-CD4i antibody specificity conferred neutralization breadth. These data provide insights into the kinetics, potency, breadth, and epitope specificity of neutralizing antibody responses in acute HIV-1 subtype C infection.

Wild Mandrillus sphinx are carriers of two types of lentivirus.

Mandrillus sphinx, a large primate living in Cameroon and Gabon and belonging to the Papionini tribe, was reported to be infected by a simian immunodeficiency virus (SIV) (SIVmndGB1) as early as 1988. Here, we have identified a second, highly divergent SIVmnd (designated SIVmnd-2). Genomic organization differs between the two viral types; SIVmnd-2 has the additional vpx gene, like other SIVs naturally infecting the Papionini tribe (SIVsm and SIVrcm) and in contrast to the other SIVmnd type (here designated SIVmnd-1), which is more closely related to SIVs infecting l'hoest (Cercopithecus lhoesti lhoesti) and sun-tailed (Cercopithecus lhoesti solatus) monkeys. Importantly, our epidemiological studies indicate a high prevalence of both types of SIVmnd; all 10 sexually mature wild-living monkeys and 3 out of 17 wild-born juveniles tested were infected. The geographic distribution of SIVmnd seems to be distinct for the two types: SIVmnd-1 viruses were exclusively identified in mandrills from central and southern Gabon, whereas SIVmnd-2 viruses were identified in monkeys from northern and western Gabon, as well as in Cameroon. SIVmnd-2 full-length sequence analysis, together with analysis of partial sequences from SIVmnd-1 and SIVmnd-2 from wild-born or wild-living mandrills, shows that the gag and pol regions of SIVmnd-2 are closest to those of SIVrcm, isolated from red-capped mangabeys (Cercocebus torquatus), while the env gene is closest to that of SIVmnd-1. pol and env sequence analyses of SIV from a related Papionini species, the drill (Mandrillus leucophaeus), shows a closer relationship of SIVdrl to SIVmnd-2 than to SIVmnd-1. Epidemiological surveys of human immunodeficiency virus revealed a case in Cameroon of a human infected by a virus serologically related to SIVmnd, raising the possibility that mandrills represent a viral reservoir for humans similar to sooty mangabeys in Western Africa and chimpanzees in Central Africa.

Characterization of a novel simian immunodeficiency virus from guereza colobus monkeys (Colobus guereza) in Cameroon: a new lineage in the nonhuman primate lentivirus family.

Exploration of the diversity among primate lentiviruses is necessary to elucidate the origins and evolution of immunodeficiency viruses. During a serological survey in Cameroon, we screened 25 wild-born guereza colobus monkeys (Colobus guereza) and identified 7 with HIV/SIV cross-reactive antibodies. In this study, we describe a novel lentivirus, named SIVcol, prevalent in guereza colobus monkeys. Genetic analysis revealed that SIVcol was very distinct from all other known SIV/HIV isolates, with average amino acid identities of 40% for Gag, 50% for Pol, 28% for Env, and around 25% for proteins encoded by five other genes. Phylogenetic analyses confirmed that SIVcol is genetically distinct from other previously characterized primate lentiviruses and clusters independently, forming a novel lineage, the sixth in the current classification. Cercopithecidae monkeys (Old World monkeys) are subdivided into two subfamilies, the Colobinae and the Cercopithecinae, and, so far, all Cercopithecidae monkeys from which lentiviruses have been isolated belong to the Cercopithecinae subfamily. Therefore, SIVcol from guereza colobus monkeys (C. guereza) is the first primate lentivirus identified in the Colobinae subfamily and the divergence of SIVcol may reflect divergence of the host lineage.

The identification of a complex A/G/I/J recombinant HIV type 1 virus in various West African countries.

In this sequence note we describe the full-length genome sequence of an HIV-1 isolate originating from the west African country of Mali. The phylogenetic tree analysis from the near full-length genome shows that the 95ML84 strain forms a separate cluster, supported by 100% of the bootstrap values, with the previously described A/G/J/? mosaic virus BFP90 from Burkina Faso. Additional analysis showed that throughout the genome the lowest diversity was seen between the 95ML84 and the BFP90 viruses, and bootscan analysis showed a similar complex genomic structure. In addition to the initial report describing the BFP90 virus as an A/G/J/? recombinant, our data show that for the BFP90 and 95ML84 strains the unclassified region corresponds to subtype I. The A/G/I/J BFP90 and 95ML84 strains represent the fifth and most complex circulating recombinant form of HIV-1 detected so far, and our data show its presence in various West African countries. Subtype I and J sequences, initially considered rare, seem to have broadened their geographical spread by way of these recombinant forms.

Ganciclovir resistance and UL97 gene mutations in cytomegalovirus blood isolates from patients with AIDS treated with ganciclovir.

BACKGROUND: Treatment of cytomegalovirus (CMV) diseases with protracted administration of ganciclovir can promote the development of resistant CMV that is associated with a poor response to therapy. It has been shown that the majority of ganciclovir-resistant CMV isolates carry mutations in the UL97 phosphotransferase gene. OBJECTIVES: To evaluate the frequency of CMV resistance to ganciclovir in patients with AIDS treated with ganciclovir and to identify the UL97 gene mutations associated with ganciclovir resistance. STUDY DESIGN: Analysis of CMV blood isolates obtained over 1 year from patients treated with ganciclovir. CMV susceptibility to ganciclovir was determined by an immediate early antigen plaque reduction assay; UL97 gene mutations were identified by restriction enzyme digest analysis and sequencing. RESULTS: Twenty-nine patients were followed-up; 17 CMV blood isolates were obtained from 10 ganciclovir-experienced patients. Thirteen (76%) of these isolates, obtained from seven (24%) patients after a median treatment duration of 5.5 months, were resistant to ganciclovir. Five of the seven patients who had a ganciclovir-resistant CMV in blood showed retinitis progression. UL97 gene mutations were identified in nine CMV isolates at codons 460 (M --> V), 594 (A --> V and A --> T), and 595(L --> S). Three patients developed a ganciclovir-resistant virus after a ganciclovir treatment shorter than 60 days (28-58 days). In another patient, we observed that ganciclovir resistance persisted 4 months after discontinuation of ganciclovir therapy. CONCLUSION: Our results indicate that ganciclovir resistance due to UL97 gene mutations is common in subjects with AIDS-related CMV diseases treated with ganciclovir. Detection of these mutations represents a tool for the management of patients with ganciclovir therapy.

An isolate of human immunodeficiency virus type 1 originally classified as subtype I represents a complex mosaic comprising three different group M subtypes (A, G, and I).

Full-length reference clones and sequences are currently available for eight human immunodeficiency virus type 1 (HIV-1) group M subtypes (A through H), but none have been reported for subtypes I and J, which have only been identified in a few individuals. Phylogenetic information for subtype I, in particular, is limited since only about 400 bp of env gene sequences have been determined for just two epidemiologically linked viruses infecting a couple who were heterosexual intravenous drug users from Cyprus. To characterize subtype I in greater detail, we employed long-range PCR to clone a full-length provirus (94CY032.3) from an isolate obtained from one of the individuals originally reported to be infected with this subtype. Phylogenetic analysis of C2-V3 env gene sequences confirmed that 94CY032.3 was closely related to sequences previously classified as subtype I. However, analysis of the remainder of its genome revealed various regions in which 94CY032.3 was significantly clustered with either subtype A or subtype G. Only sequences located in vpr and nef, as well as the middle portions of pol and env, formed independent lineages roughly equidistant from all other known subtypes. Since these latter regions most likely have a common origin, we classify them all as subtype I. These results thus indicate that the originally reported prototypic subtype I isolate 94CY032 represents a triple recombinant (A/G/I) with at least 11 points of recombination crossover. We also screened HIV-1 recombinants with regions of uncertain subtype assignment for the presence of subtype I sequences. This analysis revealed that two of the earliest mosaics from Africa, Z321B (A/G/?) and MAL (A/D/?), contain short segments of sequence which clustered closely with the subtype I domains of 94CY032.3. Since Z321 was isolated in 1976, subtype I as well as subtypes A and G must have existed in Central Africa prior to that date. The discovery of subtype I in HIV-1 hybrids from widely distant geographic locations also suggests a more widespread distribution of this virus subtype, or at least segments of it, than previously recognized.

Genetic characterization of accessory genes from human immunodeficiency virus type 1 group O strains.

Human immunodeficiency virus type 1 (HIV-1) group O strains have been described as highly divergent, compared with the vast majority of the viruses involved in the worldwide AIDS pandemic, classified in group M. To gain new insights into the diversity and genetic characteristics of group O, we have sequenced the accessory gene region (from vif to vpu) of 14 isolates. Analyses of the deduced amino acid sequences for Vif, Vpr, the first exon of Tat, and Vpu indicate that most of the functional domains of these proteins, as described for group M viruses, are highly conserved and retained among all the group O strains we have characterized. The only difference concerns the Vif phosphorylation sites, which are absent in all of the group O isolates we have sequenced; in contrast, they are well conserved in nearly all of the group M isolates, in which they play critical roles in the regulation of viral replication and infectivity. As already observed for group M isolates, the Vpu protein is also highly diverse among group O strains. Phylogenetic analyses of these sequences indicate that HIV-1 group O can be separated into four different clusters, containing most of the strains we have characterized (except one, which clusters outside of the analyzed viruses). Taking into account the criteria used for clades in group M, we were not able to define group O clades definitively.

Multiply spliced env and nef transcripts of simian immunodeficiency virus from West African green monkey (SIVagm-sab).

We have characterized the spliced transcripts of nef and envelope genes of SIVagm from African green monkey of the sabaeus subspecies. Most of the transcripts we have studied, representing the most abundant mRNA species in our assay, have undergone a specific splicing event that removes a part of the trans-activation response (TAR) element. This region is predicted to form a stable secondary structure (four stem-loop elements in SIVagm-sab) that affects the trans-activation of viral gene expression by Tat and the translation of the viral transcripts. Contrary to what is observed in other viruses, in which this R-region splicing has also been described (e.g., HIV-2), the LTR splicing in SIVagm-sab removes part of the first stem-loop and the following ones, nearly completely disrupting the TAR element secondary structure. Because LTR splicing seems to be a conserved feature among the strains we have characterized, these results suggest that this phenomenon could have important consequences for virus replication, pathogenicity, and latency.

Genetic subtypes of HIV type 1 and HIV type 2 strains in commercial sex workers from Bamako, Mali.

In Africa the highest HIV infection rate has been reported among female commercial sex workers (CSWs) who are at increasing risk of acquiring and transmitting HIV infection. In October 1995, 176 CSWs were studied in Bamako, the capital city of Mali. The ages of the CSWs ranged from 15 to 50 years old (mean, 28.8 years). Only 20.45% of the 176 CSWs were Malian; the majority were from Nigeria (32.9%) and Ghana (31.8%), and the remaining were from other African countries. Forty-one percent were active for less than 1 year as a commercial sex worker, and the length of prostitution for the remaining women ranged from 1 to 15 years (mean, 2.76). A total of 81 (46.02%) of the 176 CSWs were positive for HIV antibodies; 63 (35.8%) were HIV-1 positive, (3.9%) were HIV-2 positive, 11 (6.2%) had antibodies to HIV-1 and HIV-2, and none of them had antibodies to group O viruses. For all HIV antibody-positive samples, PBMCs were separated and genetic subtypes of HIV-1 were determined using the heteroduplex mobility assay (HMA), with ED5-ED12 as outer and ES7-ES8 as inner primers. Among the 66 HIV-1 strains characterized, 53 (80.3%) were subtype A, 2 (3.1%) belonged to subtype C, 1 (1.5%) belonged to subtype D, and 10 (15.1%) were identified as subtype G. Among the 10 subtype G strains, 8 were obtained from women who were very recent CSWs, with an activity of 1 year or less, assuming that there is a high probability that these infections occurred recently. Genetic subtypes of five HIV-2 viruses were determined by sequencing of the env and/or gag genes followed by phylogenetic analysis, and all of them belonged to subtype A. Comparison of HIV-1 and HIV-2 seroprevalence data from our study with previous data from Mali shows a significant rise in HIV-1 prevalence and a significant decrease in HIV-2 prevalence and confirms similar trends observed in neighboring countries. We have found four different genetic subtypes of HIV-1; however, subtype A is predominant and accounts for 80% of the cases and 15% of the HIV-1 infections were subtype G. It is important to continue the surveillance of subtypes on a systematic basis in order to see to what extent the proportions of the different subtypes will change over time.

PIP: The genetic variability of HIV-1 was investigated in a 1995 study of 176 commercial sex workers (CSWs) recruited in different areas in Bamako, Mali. 36 CSWs (20.45%) were born in Mali; 58 (32.9%) were from Nigeria and 56 (31.8%) were from Ghana. They ranged in age from 15-50 years (mean, 28.8 years). 41% of sex workers had been active for less than 12 months; the remaining women had been CSWs for 1-15 years (mean, 2.76 years). Of the 81 CSWs (46.02%) who were HIV-positive, 63 (35.8%) were infected with HIV-1, 7 (3.9%) with HIV-2, and the remaining 11 (6.2%) had antibodies to both HIV-1 and HIV-2. In contrast to other studies conducted among CSWs in Africa, none of these sex workers had antibodies to group O viruses. HIV-1 prevalence increased with age and length of time in prostitution and was higher among women with a history of sexually transmitted diseases. Among the 66 HIV-1 strains characterized, 53 (80.3%) were subtype A, 2 (3.1%) belonged to subtype C, 1 (1.5%) belonged to subtype D, and 10 (15.1%) were identified as subtype G. These results indicate a significant rise in HIV-1 prevalence and significant decreases in HIV-2 and combined HIV-1 and HIV-2 prevalence (10%, 15%, and 13%, respectively, in 1985). Ongoing surveillance of HIV-1 subtypes in Africa is important to identify shifts in the proportions of different subtypes over time. The genetic diversity of HIV has important implications for vaccine development.

Detection of HIV-1 RNA in two consecutive blood donations screened negative for HIV antibodies.

BACKGROUND AND OBJECTIVES: An unusual serological pattern of HIV-1 seroconversion in a blood donor is described. The seroconversion panel was used to investigate the sensitivity of existing screening assays. MATERIALS AND METHODS: A volunteer blood donor who had given blood 79 times was diagnosed anti-HIV-1-antibody-positive. The heteroduplex mobility assay identified a subtype B HIV-1 strain. The frozen plasmas from the last four blood donations had been kept at -30 degrees C. They were thawed and aliquoted for subsequent testing. RESULTS: The last two blood donations contained HIV-1 RNA, 2,800 copies/ml (October 26) and 170 copies/ml (November 23). Weak anti-p24 antibodies were detected by Western blot in the October 26 sample, and a clear p24 reactivity along with a faint gp160 reactivity was observed on November 23. HIV p24 antigen was undetectable in both samples. Out of 13 screening assays, only 6 gave positive results on the November sample and 7 negative results which were obtained by 1 competitive enzyme immunoassay (EIA) and 6 of the 9 sandwich EIAs. CONCLUSION: Most sandwich EIAs gave prolonged false-negative results in the present case. p24 antigen testing was negative and would not have reduced the risk of HIV transmission.

Geographical distribution of HIV-1 group O viruses in Africa.

OBJECTIVE: To determine to what extent HIV-1 group O strains are present in different African countries. MATERIALS AND METHODS: A total of 14,682 samples of sera from a range of patients from 12 different African countries were tested. All the sera were tested with an enzyme-linked immunosorbent assay (ELISA) using a combination of V3 peptides from ANT-70 and MVP-5180. Samples reactive in ELISA were retested in a line immunoassay (LIA-O). Samples reactive in ELISA were also retested with an in-house Western blot to determine the presence of antibodies to gp120 of HIV-1 ANT-70. Polymerase chain reaction was performed on HIV-1 group O and group O indeterminate sera. RESULTS: Of all the sera samples tested, only 19 sera had antibodies to group O V3 peptides exclusively and 46 were indeterminate for group O infection in LIA-O. The highest prevalence of HIV-1 group O infection among HIV-positive sera was observed in Cameroon (2.1%) and neighbouring countries, 1.1% in Nigeria and 0.9% in Gabon. The lowest rates were seen in west Africa: 0.07% in Senegal, 0.14% in Togo, 0.16% in Chad and 0.3% in Niger. Group O sera were observed in almost all the population categories tested. The ANT-70 V3 peptide in LIA-O was reactive with all of the sera considered to be HIV-1 group O antibody positive by LIA, versus 78.9% for the MVP-5180 peptide. Thirteen out of 19 group O samples of sera were tested in PCR. Eight samples were identified as group O by specific group O pol and/or V3 primers; in the remaining five samples no HIV RNA could be detected. Of the indeterminate sera samples, two were identified as group O. CONCLUSION: In eight of the 12 countries tested, antibodies to group O viruses were identified. Numbers of HIV-1 group O viruses are low. Their presence is not restricted to Cameroon and neighbouring countries but can also be found in west and south-east Africa.

PIP: An enzyme-linked immunosorbent assay (ELISA), using a combination of V3 peptides and ANT-70 and MVP-5180, was used to test 14,682 sera samples from people living in Burkina Faso, Burundi, Cameroon, Chad, Congo, Gabon, Mali, Niger, Nigeria, Senegal, Togo, and Zambia to examine the geographic spread of HIV-1 group O viruses in Africa. An in-house Western blot and a line immunoassay (LIA-O) were used to detect the presence of antibodies to gp120 of HIV-1 ANT-70 of samples reactive in ELISA and then a polymerase chain reaction (PCR) on HIV-1 group O and group O indeterminant sera. HIV-1 group O antibodies were present in 8 countries (Cameroon, Chad, Gabon, Niger, Nigeria, Senegal, Togo, and Zambia). Among these 8 countries, the prevalence of HIV-1 group O sera ranged from 2.1% in Cameroon to 0.07% in Senegal. Cameroon and its neighboring countries had a higher prevalence than the West African countries (0.9-2.1% vs. 0.07-0.3%) and Zambia. HIV-1 group O virus was more or less evenly distributed among the population groups tested. The ANT-70 V3 peptide in LIA-O had a higher reactivity rate with HIV-1 group O sera than MVP-5180 V3 peptide in LIA-O (100% vs. 78.9%). 8 of the 13 samples tested in PCR were identified as group O by specific group O pol and/or V3 primers. Among the remaining 5 indeterminant sera samples, 2 were identified as group O. Prospective studies are needed to monitor the true prevalence of HIV-1 group O viruses in Cameroon, its neighboring countries, and West Africa. They are also needed to determine the risk factors associated with group O infection. Monitoring these viruses will allow adaptation of HIV testing strategies for blood screening and serodiagnosis if required.

Presence of multiple non-B subtypes and divergent subtype B strains of HIV-1 in individuals infected after overseas deployment.

OBJECTIVE: To identify the genetic subtypes and characteristics of HIV-1 strains from individuals infected after overseas deployment. PATIENTS AND METHODS: Sixty-one HIV-1-positive individuals detected between 1986 and 1995 in the French army were included in the study. For each patient, the year and country of HIV infection are known. Genetic subtypes of HIV-1 were determined using the heteroduplex mobility assay (HMA) using ED5/ED12 as outer and ES7/ES8 as inner primers. Strains were further characterized by sequencing and phylogenetic analysis of the C2-V3 region. The amino-acid sequences corresponding to the V3 region were aligned on the basis of the subtyping results and were then compared to the consensus V3 sequences of the corresponding subtypes. RESULTS: Among the 61 patients studied, nine became infected in France, and 52 were HIV-negative before overseas deployment but HIV-positive at their return. The majority (n = 43) deployed in Africa and a limited number of patients deployed in Asia (Cambodia, n = 5) or South America (guyana, n = 4). The nine individuals who were not deployed overseas were all infected with subtype B strains. The majority of the other patients were infected with non-B strains; eight subtype A, 20 subtype B, 16 subtype C, one subtype D, six subtype E and one subtype F. Five of the six subtype E strains were contracted in Cambodia and one in Djibouti, and all subtype C strains were from Djibouti. Phylogenetic analysis revealed a large diversity among the different strains introduced into France. Analysis of the amino-acid sequences of the V3 loop revealed the introduction of uncommon V3-loop patterns. CONCLUSION: In the group of HIV-1-infected individuals that we studied and who were deployed overseas, 63.4% were infected with non-B strains. In addition, the subtype A, B and C viruses in this population were very heterogeneous. Due to the routine occurrence of international travel and deployment, the predominance of subtype B HIV-1 viruses may change in European countries. However, the possible implications on the dynamics of the HIV-1 epidemic needs further follow-up.

Genetic diversity of simian immunodeficiency viruses from West African green monkeys: evidence of multiple genotypes within populations from the same geographical locale.

High simian immunodeficiency virus (SIV) seroprevalence rates have been reported in the different African green monkey (AGM) subspecies. Genetic diversity of these viruses far exceeds the diversity observed in the other lentivirus-infected human and nonhuman primates and is thought to reflect ancient introduction of SIV in the AGM population. We investigate here genetic diversity of SIVagm in wild-living AGM populations from the same geographical locale (i.e., sympatric population) in Senegal. For 11 new strains, we PCR amplified and sequenced two regions of the genome spanning the first tat exon and part of the transmembrane glycoprotein. Phylogenetic analysis of these sequences shows that viruses found in sympatric populations cluster into distinct lineages, with at least two distinct genotypes in each troop. These data strongly suggest an ancient introduction of these divergent viruses in the AGM population.

Simian immunodeficiency virus infection in a patas monkey (Erythrocebus patas): evidence for cross-species transmission from African green monkeys (Cercopithecus aethiops sabaeus) in the wild.

Socio-ethological studies on troops of African green monkeys (AGMs) (Cercopithecus aethiops sabaeus) and patas monkeys (Erythrocebus patas) in Senegal have documented physical contacts between these two species. Elevated simian immunodeficiency virus (SIV) seroprevalence rates have been reported for the different AGM subspecies. We report here the extent to which patas monkeys are infected and compare the relatedness of the viruses isolated from theses two different species. Among the 85 AGMs and 54 patas monkeys studied, 47% of 7.5%, respectively, had antibodies that cross-reacted with HIV-2 envelope proteins. From two AGMs a virus was isolated. From the patas monkeys, virus isolation was generally not possible, but from one animal that was ill a virus designated pamG31 was amplified by PCR. In addition, for the two SIVagm isolates, an 830 bp region spanning the env and nef genes was amplified and sequenced. Comparisons of sequences from the env/nef region revealed 80% identity between pam G31 and SIVagm isolates from AGMs of the sabaeus subspecies, and 94% identity between the two SIVagm isolates. Phylogenetic analysis showed that pamG31 belongs to the SIVagm sabaeus subgroup. This is the first report of a lentiviral infection in a patas monkey. The close genetic relatedness between pamG31 and SIVagm sabaeus viruses is a strong argument in favour of cross-species transmission of SIV between AGMs and patas monkeys in the wild. For these reasons, we propose to refer to this patas virus as SIVagm-pamG31.

Regulatory genes of simian immunodeficiency viruses from west African green monkeys (Cercopithecus aethiops sabaeus).

The high seroprevalence of simian immunodeficiency viruses (SIVs) in African green monkeys (AGMs) without immunological defects in their natural hosts has prompted consideration of SIV-infected AGMs as a model of apathogenic SIV infection. Study of the molecular mechanisms of SIVagm asymptomatic infection could thus provide clues for understanding the pathogenesis of human immunodeficiency viruses. Regulatory genes could be candidates for genetic control of SIVagm apathogenicity. We have characterized Vpr, Tat, Rev, and Nef genes of two SIVagm strains isolated from naturally infected sabaeus monkeys captured in Senegal. The results provide further evidence that SIVagm from West African green monkeys is the most divergent class of AGM viruses, with structural features in long terminal repeat sequences and Vpr and Tat genes that distinguish them from viruses isolated from other AGM species (vervet, grivet, and tantalus monkeys).

Serum, AP-1 and Ets-1 stimulate the human ets-1 promoter.

The ets-1 proto-oncogene codes for a transcription factor. In order to understand how ets-1 is regulated, we have cloned its promoter. We show that the promoter is inducible by serum and expression of c-Fos and c-Jun, and it is positively auto-regulated by its gene product. A 50 base-pair sequence is sufficient to confer c-Fos + c-Jun and c-Ets-1 responsiveness to a heterologous promoter. This element contains two AP1 and one Ets-1 like motifs. Striking, AP-1 and Ets-1 motifs are found in oncogene responsive units (ORU's) of other promoters, suggesting that combining these motifs is a common mechanism for generating mitogen responsive transcription elements.