HIV superinfection

A study conducted in Kenya in 2007 shows that superinfection tends to occur during the course of the initial infection, that is during acute infection, or 1–5 years after initial infection, but not during the latency period.[5] Thus, superinfection occurs after an immune response to the initial infection has already been established.[5]

It is unknown what aspects of the natural immune response to HIV may protect someone from superinfection, but it has been shown that cytotoxic lymphocyte responses do not seem to be protective.[6] Immune responses to initial infection with a particular strain of HIV do not provide protection against superinfection with a different strain.[5] The effect of neutralizing antibodies (NAb) is also unknown, but it has been shown that individuals with HIV tend not to have a NAb response prior to superinfection.[1]

In addition, it has been demonstrated that superinfection can occur in individuals that demonstrate a robust anti-HIV antibody response. The anti-HIV antibody response broadens and strengthens in individuals post-superinfection.[7] The finding that superinfection occurs within and between HIV subtypes suggests that an immune response to initial HIV infection provide limited protection against infection by a new viral strain.[3] This means that HIV-vaccine strategies made to replicate the host's immune response to HIV infection may not prevent new infections.

Studies indicate that superinfection causes a spike in HIV viral load and a decrease in CD4+ cell count similar to those reported during primary HIV infection.[3][8] Early studies of HIV superinfection analysed these spikes to diagnose cases of superinfection.[3] It is unclear whether superinfection causes a sustained increase in viral load.[3] The effect of superinfection on the progression of HIV infection is unclear because of its ambiguous effects on surrogate markers for the disease, such as an increase in viral load or a decrease in CD4 cell count.[1] The potential of superinfection to cause rapid disease progression depends on viral and host factors.[3]

Cases of superinfection are yet to be identified in sufficient numbers to conduct detailed studies on the effect of superinfection on the host immune response.[3]

HIV superinfection is distinct from HIV dual infection, where an individual is simultaneously infected with multiple distinct viral strains. HIV superinfection involves an individual with HIV being infected by a new, phylogenetically distinct HIV strain.[3] Early reports of HIV superinfection were observed in cases of co-infection with HIV-1 and HIV-2.[3]

Studies have shown that a lack of neutralizing antibodies against HIV-1 infection predisposes patients to superinfection.[3] Additionally, the tendency of HIV-1 virions to recombine when two subtypes infect a single cell increases its susceptibility to HIV superinfection.[3] Further evidence of superinfection stems from the fact that nearly 10% of HIV-1 infections are associated with a transmittable recombinant strain.[3] HIV-1 virions are divided into nine subtypes, all of which are characterized by different rates of disease progression, viral load and sensitivity to assays used in detection.[3] When a single cell is infected by two HIV-1 subtypes, they recombine, forming a new, transmittable recombinant strain.[3]

Initial reports solely documented interclade superinfection, where patients are infected by a virus of a different clade from the initial virus.[1] This is because the viruses in initial cases were all subtypes of HIV-1, with at least a 30% difference in nucleotides in their envelope proteins that makes such superinfections easier to detect.[1]

Superinfection is identified by the detection of viral recombinants for phylogenetically distinct parent strains.[2]

Multiregion hybridisation assays are used to identify interclade superinfection by detecting genetic differences between parental and progeny strains.[3] Heteroduplex mobility assays can be used to sequence viral genetic material, allowing the detection of samples with a genetic difference exceeding 1.5%.[3]

Bulk sequencing is used to amplify viral RNA to enable the identification of new phylogenetic species in a patient over time.[3] However, this method is poor at detecting genetic differences at levels of 20% of lower.[3]

A third method, next-generation-sequencing assays, was developed in 2005.[13] It enables the rapid sequencing and screening of genomes, detecting genetic differences of 1% or less.[3]

There are no known methods to estimate the timing of superinfection.[3]

Studies on individuals with superinfection with 2 strains of HIV showed a poorer prognosis.[14] Superinfection is correlated with a faster progression of the HIV infection.[14] Patients in studies have displayed a shorter lag between seroconversion and experiencing an AIDS-defining clinical condition or death.[14] However, it is unclear whether this rapid conversion is a direct effect of superinfection, or a result of a weaker immune response to the virus caused by superinfection.[14]

It is difficult to gain accurate estimations of the frequency of HIV superinfection because most studies are performed on patients infected with the HIV-1 B subtype, and recombinant strains are difficult to distinguish from the original strain for this subtype.[15]

HIV superinfection has been reported in the US, Canada, Europe, Australia, Asia, and Africa.[3] Data on the prevalence of superinfection has been gathered from case reports and observational studies, suggesting that it is underreported.[3]

Initial care reports and observational studies of superinfection were in men who have sex with men, intravenous drug users and female sex workers.[3] Incidence in heterosexual populations was first reported in rural Africa.[3]

Incidence rates have been reported as 0% to 7.7% annually, although this varies across populations and depends on the frequency of antiretroviral drug use, the length of the follow-up period, and the method used to detect superinfection.[3] However, a study in Uganda conducted using next-generation deep sequencing assays found that the rate of superinfection was large enough to be comparable to the primary HIV infection rate.[2]

Risk factors for superinfection are not clearly understood because of the small number of cases documented.[3] However, the risk factors for primary infection are considered to apply to superinfection, including:

• high number of sexual partners[3]
• limited condom use[3]
• no anti-retroviral use[3]
• detectable plasma viral load[16]
• absence of male circumcision[3]
• non-marital relationships[3]

The results of studies modeling the effect of HIV superinfection on viral recombination have suggested that superinfection has been instrumental in spurring community recombination rates.[17] However, these studies were based on several epidemiological assumptions that are yet to be verified.[17] These include assumptions about the pattern of HIV-1 transmission and that superinfection causes transmission to uninfected sexual partners.[3]

1987 - First evidence of superinfection reported in studies of chimpanzees.[18]

1991 - HIV-1 found to superinfect HIV-2-infected cells in a study through inducing infection in cells cultured from HIV patient samples.[19]

1999 - In pig tailed macaques, a "window of susceptibility" demonstrated by showing that superinfection with a new viral strain was only possible after initial infection in macaques.[20]

2002 - First definitive study on superinfection after cases reported in IV drug users in Bangkok, Thailand.[21] The initial cases were all interclade superinfections.[21]

2003 - Intraclade infection by an immune response to one strain of HIV-1 cannot prevent superinfection with a second virus from the same clade.[22]

2005 - The ability of HIV superinfection to cause ART resistance.[11]