HIV-1 Dual Infection: Real or Imagined?

Davey Smith, MD, MAS
Associate Professor of Medicine
University of California at San Diego
La Jolla, California



Lentiviral dual infection occurs with simian immunodeficiency virus (SIV) and HIV-2 in macaques, HIV-1 in chimpanzees, and feline immunodeficiency virus in cats,1-5 suggesting that HIV-1 dual infection should not be unexpected in humans. The best circumstantial evidence for HIV dual infection is that 10% of HIV infections worldwide involve recombinant viruses.6 Ramos et al reported the first confirmed case of HIV dual infection in humans in 2002.7 There has also been one report of HIV triple infection,8 and a report of infection with HIV-2.9 The initial reports involved people who were dually infected with a virus from a clade different from their initial infecting virus (interclade).7, 10 Because HIV-1 clades can be differentiated genetically, interclade superinfections can be readily detected by molecular methods; immune responses to the initial infection might be less likely to protect against such a divergent superinfecting virus. Subsequently, however, superinfection with the same clade (intraclade) was reported by my group and others.11, 12

What is the Difference Between HIV Coinfection and Superinfection? Top of page


Similar to other persistent viral infections, such as cytomegalovirus, Epstein-Barr virus, and hepatitis C virus, infection of an individual with a second viral strain (dual infection)13-15 may also occur in HIV infection. Dual infection, which can be classified as either coinfection or superinfection, occurs when an individual is infected with strains derived from two different individuals.
Dual infection can be classified as either coinfection or superinfection:

  • Coinfection is infection with two separate strains either simultaneously or within a brief period of time before infection with the first strain is established.
  • Superinfection is sequential infection with a heterologous strain after an immune response has been established to the initial strain.16 The term "superinfection" does not mean that the second infection is stronger or more virulent; it is meant to distinguish dual infection from instances of re-infection after the first virus has cleared, as occurs with most respiratory viruses,17 but not with HIV.

 

What Can We Learn from HIV Superinfection?Top of page

While HIV superinfection may not precisely reflect initial infection after vaccination, perhaps developers of HIV vaccines should consider instances in which the immune response to the initial infection was unable to protect against the second viral challenge.16, 44, 54 Specifically, a better understanding of the roles of cytotoxic T-cell and neutralizing-antibody responses in controlling or preventing secondary infections or superinfections could help in the design of therapeutic and preventive vaccines.55, 56

Initial investigations into the cytotoxic T-cell responses before and after HIV superinfection found that the individual’s immune response had good control of the initial virus, with low viral loads and high CD4+ counts. However, after superinfection, there was a poor cytotoxic response to the superinfecting virus, and an associated rise in viral load, and decrease in CD4+ counts.7, 12, 57 In these cases, the superinfecting virus did not share apparently important epitopes with the first virus, which could explain how the superinfecting virus became the predominant strain. These data may not support the development of a vaccine based on cytotoxic T-cell responses, and may explain why Merck’s V520 HIV vaccine did not offer substantial protection.58 On the other hand, initial case control investigations into neutralizing antibodies among small cohorts of highly exposed individuals found that those with higher levels of cross-reactive neutralizing antibodies did not become superinfected, while individuals with low levels of neutralizing antibodies did.59 Although these observations were not replicated among individuals superinfected by HIV-1 clades that were different than their initial infection.54 Further studies are required in larger prospective cohorts to delineate the true role of neutralizing antibody in protection against superinfection, and how cross-reactive this neutralizing antibody response must be to offer a realistic level of protection against an initially infecting strain, as in the setting of a preventive vaccine, or against a superinfecting strain. This may be extremely difficult considering the genetic diversity of HIV-1 worldwide.42

ReferencesTop of page

1.  Otten RA, Ellenberger DL, Adams DR, et al. Identification of a window period for susceptibility to dual infection with two distinct human immunodeficiency virus type 2 isolates in a Macaca nemestrina (pig-tailed macaque) model. J Infect Dis. 1999;180(3):673-684.

2.  Petry H, Dittmer U, Stahl-Hennig C, et al. Reactivation of human immunodeficiency virus type 2 in macaques after simian immunodeficiency virus SIVmac superinfection. J Virol. 1995;69(3):1564-1574.

3.   Wakrim L, Le Grand R, Vaslin B, et al. Superinfection of HIV-2-preinfected macaques after rectal exposure to a primary isolate of SIVmac251. Virology. 1996;221(2):260-270.

4.   Fultz PN, Srinivasan A, Greene CR, Butler D, Swenson RB, McClure HM. Superinfection of a chimpanzee with a second strain of human immunodeficiency virus. J Virol. 1987;61:4026-4029.

5.   Okada S, Pu R, Young E, Stoffs WV, Yamamoto JK. Superinfection of cats with feline immunodeficiency virus subtypes A and B. AIDS Res Hum Retroviruses. 1994;10(12):1739-1746.

6.   Robertson DL, Anderson JP, Bradac JA, et al. HIV-1 nomenclature proposal. Science. 2000;288(5463):55-56.

7.   Ramos A, Hu DJ, Nguyen L, et al. Intersubtype human immunodeficiency virus type 1 superinfection following seroconversion to prmary infection in two injection drug users. J Virol. 2002;76(15):7444-7452.

8.   van der Kuyl AC, Kozaczynska K, van den Burg R, et al. Triple HIV-1infection. N Engl J Med. 2005;352(24):2557-2559.

9.   Huber M, Boni J, Schupbach J, Guenthard H. Superinfection of an HIV-2 infected woman by HIV-1. Int J Inf Dis. 2006;10:S38.

10.     Jost S, Bernard MC, Kaiser L, et al. A patient with HIV-1 superinfection. N Engl J Med. 2002;347(10):731-736.

11.     Koelsch KK, Smith DM, Little SJ, et al. Clade B HIV-1 superinfection with wild-type virus after primary infection with drug-resistant clade B virus. AIDS. 2003;17(7):F11-16.

12.    Altfeld M, Allen TM, Yu XG, et al. HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature. 2002;420(6914):434-439.

13.   Chandler SH, Handsfield HH,McDougall JK. Isolation of multiple strains of cytomegalovirus from women attending a clinic for sexually transmitted disease. J Inf Dis. 1987;155(4):655-660.

14.    Herring BL, Page-Shafer K, Tobler LH, Delwart EL. Frequent hepatitis C virus superinfection in injection drug users. J Inf Dis. 2004;190(8):1396-1403.

15.     Apolloni A, Sculley TB. Detection of A-type and B-type Epstein-Barr virus in throat washings and lymphocytes. Virology. 1994;202(2):978-981.

16.    Smith DM, Richman DD, Little SJ. HIV superinfection. J Inf Dis. 2005;192(3):438-444.

17.    Majer M. Immunity after infections with Myxoviruses. Infection. 1976;4(2):80-83.

18.    Gonzales MJ, Delwart E, Rhee SY, et al. Lack of detectable human immunodeficiency virus type 1 superinfection during 1072 person-years of observation. J Inf Dis. 2003;188(3):397-405.

19.    Tsui R, Herring BL, Barbour JD, et al. Human immunodeficiency virus type 1 superinfection was not detected following 215 years of injection drug user exposure. J Virol. 2004;78(1):94-103.

20.    Allen T, Altfeld M. HIV-1 superinfection. J Allergy Clin Immunol. 2003;112(5):829-835.

21.     Gottlieb GS, Nickle DC, Jensen MA, et al. Dual HIV-1 infection associated with rapid disease progression. Lancet. 2004;363(9409):619-622.

22.     Gottlieb GS, Nickle DC, Jensen MA, et al. HIV type 1 superinfection with a dual-tropic virus and rapid progression to AIDS: a case report. Clin Infect Dis. 2007;45(4):501-509.

23.    Smith DM, Wong JK, Hightower GK, et al. Incidence of HIV superinfection following primary infection. JAMA. 2004;292(10):1177-1178.

24.    Yerly S, Jost S, Monnat M, et al. HIV-1 co/super-infection in intravenous drug users. AIDS. 2004;18(10):1413-1421.

25.    Cornelissen M, Jurriaans S, Kozaczynska K, et al. Routine HIV-1 genotyping as a tool to identify dual infections. AIDS. 2007;21(7):807-811.

26.    Brenner B, Routy JP, Quan YD, et al. Persistence of multidrug-resistant HIV-1 in primary infection leading to superinfection [published erratum appears in AIDS. 2004;18(15):2107]. AIDS. 2004;18(15):1653-1660.

27.    Grobler J, Gray CM, Rademeyer C, et al. Incidence of HIV-1 dual infection and its association with increased viral load set point in a cohort of HIV-1 subtype C-infected female sex workers. J Inf Dis. 2004;190(7):1355-1359.

28.    Pernas M, Casado C, Fuentes R, Perez-Elias MJ, Lopez-Galindez C. A dual superinfection and recombination within HIV-1 subtype B 12 years after primoinfection. J Acquir Immune Defic Syndr. 2006;42(1):12-18.

29.    Fang GW, Weiser B, Kuiken C, et al. Recombination following superinfection by HIV-1. AIDS. 2004;18(2):153-159.

30.    Blackard JT, Cohen DE, Mayer KH. Human immunodeficiency virus superinfection and recombination: Current state of knowledge and potential clinical consequences. Clin Infect Dis. 2002;34(8):1108-1114.

31.    Colfax GN, Guzman R, Wheeler S, et al. Beliefs about HIV reinfection (superinfection) and sexual behavior among a diverse sample of HIV-positive men who have sex with men. J Acquir Immune Defic Syndr. 2004;36(4):990-992.

32.    McConnell JJ, Grant RM, Greenwood G. Concerns about HIV superinfection and the sexual practices of seroconcordant couples. 14th International AIDS Conference. Barcelona, Spain. July 7-12, 2002. Abstract C10929.

33.    Smith DM, Wong JK, Hightower GK, et al. The clinical consequences of HIV superinfection. 15th International AIDS Conference, Bangkok,Thailand. July 11-16, 2004. Abstract TuOrB1140.

34.    Smith DM, Wong JK, Hightower GK, et al. HIV drug resistance acquired through superinfection. AIDS. 2005;19(12):1251-1256.

35.    Jurriaans S, Kozaczynska K, Zorgdrager F, et al. A sudden rise in viral load is infrequently associated with HIV-1 superinfection. J Acquir Immune Defic Syndr. 2008;47(1):69-73.

36.    Pacold M, Kosakovsky Pond S, Wagner G, Delport W, Bourque D, Little S, Richman D, Smith, D.  Clinical and virologic consequences of HIV-1 superinfection and the influence of HLA. 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA. Feb 27-Mar 3, 2011. Abstract 290.

37.     Smith DM, Wong JK, Hightower GK, et al. HIV drug resistance acquired through superinfection. AIDS. 2005;19(12):1251-1256.

38.     Pacold M, Smith D, Little S, et al. Comparison of methods to detect HIV dual infection. AIDS Res Hum Retroviruses. 2010;26(12):1291-1298.

39.     Rachinger, A., et al. Evaluation of pre-screening methods for the identification of HIV-1 superinfection. J Virol Methods. 2010;165(2):311-317.

40.     Rachinger A, Stolte IG, van de Ven TD, et al. Absence of HIV-1 superinfection 1 year after infection between 1985 and 1997 coincides with a reduction in sexual risk behavior in the seroincident Amsterdam cohort of homosexual men. Clin Infect Dis. 2010;50(9):1309-1315.

41.    Peeters M (2000). Recombinant HIV sequences: Their role in the global epidemic. pp. I 39-54 in HIV Sequence Compendium 2000. http://www.hiv.lanl.gov/content/sequence/HIV/REVIEWS/PEETERS2000/Peeters.html. Published 2000.  Accessed April 20, 2008.

42.    Burton DR. A vaccine for HIV type 1: The antibody perspective. Proc Natl Acad Sci USA. 1997;94(19):10018-10023.

43.    Chohan B, Lavreys L, Rainwater S, Sagar M, Mandaliya K, Overbaugh J. The biology of HIV-1 transmission and re-infection. Paper presented at the 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA. February 22-25, 2005. Abstract 66..

44.     Fultz PN. HIV-1 superinfections: Omens for vaccine efficacy? AIDS. 2004;18(1):115-119.

45.     Peeters M, Courgnaud V. Overview of primate lentiviruses and their evolution in non-human primates in Africa. pp. 2-23 in HIV Sequence Compendium 2002. http://www.hiv.lanl.gov/content/sequence/HIV/REVIEWS/PEETERS2002/Peeters2002.html. Published 2002. Last modified April 20, 2010.

46.    Mansky LM, Temin HM. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol. 1995;69(8):5087-5094.

47.    Malim MH, Emerman M. HIV-1 sequence variation: Drift, shift, and attenuation. Cell. 2001;104(4):469-472.

48.    Robertson DL, Sharp PM, McCutchan FE, Hahn BH. Recombination in HIV-1. Nature. 1995;374(6518):124-126.

49.    Perrin L, Kaiser L, Yerly S. Travel and the spread of HIV-1 genetic variants. Lancet Infect Dis. 2003;3(1):22-27.

50.    McCutchan FE, Hoelscher M, Tovanabutra S, et al. In-depth analysis of a heterosexually acquired human immunodeficiency virus type 1 superinfection:   Evolution, temporal fluctuation, and intercompartment dynamics from the seronegative window period through 30 months postinfection.J Virol. 2005;79(18):11693-11704.

51.    Kozaczynska K, Cornelissen M, Reiss P, et al. HIV-1 sequence evolution in vivo after superinfection with three viral strains. Retrovirology. 2007;4:59.

52.    Hemelaar J, Gouws E, Ghys PD, Osmanov S. Global and regional distribution of HIV-1 genetic subtypes and recombinants in 2004. AIDS. 2006;20(16):W13-23.

53.    Gross KL, Porco TC, Grant RM. HIV-1 superinfection and viral diversity. AIDS. 2004;18(11):1513-1520.

54.    Blish, C.A., et al. Human immunodeficiency virus type 1 superinfection occurs despite relatively robust neutralizing antibody responses. J Virol. 2008;82(24):12094-12103.

55.    Chohan BH, Piantadosi A, Overbaugh J. HIV-1 superinfection and its implications for vaccine design. Curr HIV Res. 2010;8(8):596-601.

56.    Smith DM, Richman DD, Little SJ. HIV superinfection. J Infect Dis. 2005;192(3):438-444.

57.    Yang OO, Daar ES, Jamieson BD, et al. Human immunodeficiency virus type 1 clade B superinfection: Evidence for differential immune containment of distinct clade B strains. J Virol. 2005;79(2):860-868.

58.    HIV vaccine failure prompts Merck to halt trial. Nature. 2007;449(7161):390.

59.    Smith DM, Strain MC, Frost SDW, et al. Lack of neutralizing antibody response to HIV-1 predisposes to superinfection. Virology. 2006;355(1):1-5.

 

You must be logged in to post a comment. Login | Register