Acute and early HIV infection: Pathogenesis and epidemiology

INTRODUCTION — In 1985, the first description of acute human immunodeficiency virus (HIV) infection, a "mononucleosis-like" illness, was published based upon the clinical records of 12 men with documented seroconversion to HIV during the preceding six months; 11 of these individuals experienced a remarkably similar illness [1]. Since that time, larger studies have described the clinical and laboratory features of acute and early HIV infection.

Increased awareness of the clinical spectrum of acute HIV infection and better diagnostic tests (in particular HIV RNA and the combined HIV antigen/antibody test) have led to more accurate identification of recently acquired infection. In addition, several studies now provide support for initiating antiretroviral therapy during early HIV for both individual and public health benefits.

The pathogenesis and epidemiology of acute and early HIV will be reviewed here. The clinical manifestations, diagnosis, and treatment of early HIV infection are discussed separately. (See "Acute and early HIV infection: Clinical manifestations and diagnosis" and "Acute and early HIV infection: Treatment".)

DEFINITIONS — Different terms, including acute, recent, primary, and early HIV infection, have been used in the literature to refer to variable intervals following initial infection with the virus. In this topic, we use the term "early HIV infection" to refer to the approximate six-month period following HIV acquisition. We use the term "acute HIV infection" to refer to symptomatic early infection, as this reflects common usage in clinical care.

PATHOGENESIS — HIV has several targets including dendritic cells, macrophages, and CD4+ T cells.

Target cells — HIV-1 most often enters the host through the anogenital mucosa. The viral envelope protein, glycoprotein (GP)-120, binds to the CD4 molecule on dendritic cells. Interstitial dendritic cells are found in cervicovaginal epithelium as well as tonsillar and adenoidal tissue, which may serve as initial target cells in infection transmitted via genital-oral sex [2].

Newly acquired HIV is more commonly due to transmission of macrophage tropic rather than T cell tropic viruses [3]. Viral entry into these cells is mediated by different coreceptors. In order to enter macrophages, GP-120 must bind to the chemokine receptor CCR5 as well as CD4 [4,5]. Macrophage tropic viruses are designated as R5 in comparison to T cell tropic viruses, which are called X4, based upon the CXCR4 receptor on these cells [2]. Patients homozygous for a deletion in CCR5 are relatively resistant to R5 infection, but cases of X4 infection have rarely been reported in these individuals [6-9].

HIV infected cells fuse with CD4+ T cells, leading to spread of the virus. HIV is detectable in regional lymph nodes within two days of mucosal exposure and in plasma within another three days [2]. Once virus enters the blood, there is widespread dissemination to organs such as the brain, spleen, and lymph nodes.

The intestinal mucosa is also a primary target during initial infection [10,11]. Massive CD4 T-cell depletion during acute infection has been demonstrated with simian immunodeficiency virus (SIV) in rhesus macaques [12,13]. Both studies documented that destruction occurred preferentially in CD4+ memory T cells, which may result from direct infection as well as through apoptosis. This can lead to an early and disproportionate loss of CD4+ T cells in the gastrointestinal compartment, compared to peripheral blood [14]. It has also been proposed that microbial translocation, due to changes in the gut mucosal barrier, may be the etiology of chronic immune activation in HIV infection [15,16].

Viremia — Studies in primates suggest viral penetration of mucosal epithelium, followed by infection of submucosal CD4+ T cells, dendritic cells, and macrophages with subsequent spread to lymph nodes [17] and ultimately, plasma. Viremia was documented between 5 to 30 days after experimental intravaginal simian immunodeficiency virus (SIV) exposure.

In humans, HIV RNA levels rapidly increase from the earliest quantifiable measure to a peak level that usually coincides with seroconversion [18,19]. However, a period of low-level viremia preceding ramp-up viremia, may be more common than originally thought. A study of serial samples from patients with confirmed early HIV infection was performed to determine if low levels of viremia were present in samples that were negative by prior quantitative PCR [20]. On retesting with a sensitive qualitative reverse transcriptase PCR assay with sensitivity of 4 copies/mL, 23 of 69 samples were subsequently positive. These specimens preceded the first sample with >100 copies/mL by 9 to 25 days. Whether blood is infectious at this low level of concentration is not known.

The HIV DNA level in peripheral blood mononuclear cells provides an estimate of the cellular HIV reservoir, which is established soon after infection. In one study of 163 patients who did not start immediate antiretroviral therapy after diagnosis of acute infection, the HIV DNA level and initial CD4 cell count were found to be independent predictors of disease progression [21].

Cellular immune response — At the time of initial infection with HIV, patients have a large number of susceptible CD4+ T cells and no HIV-specific immune response. Viral replication is therefore rapid; plasma HIV RNA levels may climb to more than 10(7) copies/mL and p24 antigen levels may exceed 100 pg/mL.

Concomitant with the evolution of HIV specific immunity, primarily due to the emergence of virus-specific CD8+ cytotoxic T lymphocytes, plasma RNA levels fall precipitously by 2 to 3 logs, and symptoms of the acute retroviral syndrome resolve. In the absence of antiretroviral therapy, plasma HIV RNA levels will stabilize at an individual's given "set-point" within six months of infection [22]. The host factors, virus factors, and pharmacologic interventions, which determine this set point, are active issues for ongoing investigations [2].

A few individuals with HIV may, even in the absence of antiretroviral therapy, retain normal CD4 counts and low or undetectable plasma viremia. Those with persistent viral suppression are sometimes referred to as "elite controllers." A large study from France demonstrated that this clinical phenotype was quite rare [23]. These individuals are distinguished from regular and rapid progressors by the persistence of HIV-specific T-helper cell proliferative responses. In one model, these proliferative responses allow for ongoing HIV-specific cytotoxic T lymphocyte activity and hence containment of plasma viremia. However, it is not clear whether these HIV immune responses directly cause, or alternatively, are the result of HIV control. Some research suggests that initiation of antiretroviral therapy during acute infection protects activated HIV-specific T helper cells from infection by HIV and thereby preserves the HIV-specific cytotoxic T lymphocyte response to virally infected cells, a situation analogous to the long-term nonprogressors [2].

Studies of T cell responses in early HIV infection help to delineate how early therapy might improve clinical outcomes. In one study, patients with early HIV infection who were identified early in the course of their acute disease demonstrated a 10- to 20-fold increase in the proportion of highly activated (CD38+) and proliferating (Ki-67+) CD4 T cells that expressed CCR5 [24]. CD4 T cells that produced interferon gamma in response to HIV antigens were readily detected in this patient subset. However, in patients with early HIV infection who presented later in their clinical course, antigen-specific CD4+ T cells could not be readily detected. This observation coincided with lower frequencies of activated and proliferating T cells, suggesting that apoptosis and cytopathic infection with HIV leads to their rapid decline. Regulatory T cells may also play a role in suppressing HIV-specific CD4 T cell responses in early infection [25].

Preservation of the immune response to HIV may also shorten the duration of symptoms associated with acute infection, prevent dissemination of virus to other organs, and establish a lower virologic "set-point." Despite these potential benefits, eradication of virus is unlikely with currently available agents, as studies consistently show that replication-competent HIV may be recovered even from patients with completely suppressed viral loads [26]. In addition, patients with extremely low levels of virus after prolonged virologic suppressions still experience virologic rebound when treatment is stopped [27]. Representative cases are described in detail elsewhere. (See "Acute and early HIV infection: Treatment", section on 'Can ART in early infection alter disease course?'.)

Genetic susceptibility — Cohorts of individuals who are highly exposed (people who inject drugs or commercial sex workers) but who remain HIV-seronegative have been described [28]. A nested case-control study of 266 HIV-seropositive patients and 532 seronegative controls was conducted to examine whether any of nine candidate host genes may play a role in susceptibility to HIV [29]. Self-reported risk behaviors were analyzed from data collected at semi-annual visits. Four single-nucleotide polymorphisms (CCR-2, CCR5, MIP1A, and IL2) were significantly associated with HIV susceptibility in different genetic models.

The most extensively studied of these genetic factors is the C-C chemokine receptor 5 (CCR5), a major coreceptor for HIV [5]. CCR5 (delta) 32 is an allele that contains a 32-base pair deletion and codes for a nonfunctional coreceptor. CCR5 (delta) 32 homozygotes (people who inherited the allele from both parents) are highly resistant to HIV. Patients who are heterozygous for the 32-base pair deletion can acquire HIV, but have a slower rate of progression. (See "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Factors affecting HIV disease progression'.)

EPIDEMIOLOGY

Risk factors — Symptomatic acute HIV infection has been reported in all major risk categories including men who have sex with men (MSM), people who inject drugs, blood product recipients, and health care workers with a needle-stick exposure [30]. Transmission of HIV during early infection is correlated with unprotected anal intercourse, the number of sexual contacts, and high rates of acute sexually transmitted diseases in MSM [31].

Symptomatic versus subclinical disease — It is difficult to determine the incidence of symptomatic versus subclinical early HIV infection for a number of reasons:

●It is often not possible to precisely define the time of seroconversion

●The clinical symptoms are nonspecific

●Not all febrile illnesses retrospectively identified during seroconversion will represent early HIV infection

●Patients with asymptomatic early infection often do not seek medical attention

Despite these caveats, the majority of patients with early HIV infection appear to be symptomatic. In a retrospective case-control study, 39 men who seroconverted were compared to 26 men who were seronegative during a six-month period [32]. Ninety-two percent of the men who seroconverted reported a clinical illness during the six-month interval compared to 40 percent of controls; the average duration of symptoms was 10 days longer in seroconverters and 87 percent sought medical attention. While the calculated lower limit of incidence of symptomatic acute HIV infection from this study is 53 percent based upon 40 percent of controls reporting an illness, the incidence is probably closer to the 92 percent given the distinctive nature of the syndrome reported by seroconverters.

In another study of seroconverters, identified through a surveillance program in which HIV testing was performed over six months, 20 of 23 (87 percent) individuals recalled symptoms consistent with the acute retroviral syndrome during the six-month interval containing their seroconversion. Nineteen of these patients felt ill enough to seek medical attention — 48 percent from their primary care physician, 31 percent from an emergency department, and 21 percent from a walk-in clinic [33].

There is evidence that the presence of severe symptoms during acute infection predicts more rapid clinical progression to acquired immunodeficiency syndrome AIDS [34,35].

Infectivity — Patients with early HIV infection are highly contagious to others, given the typical transiently high viral loads seen in early HIV infection. Blood HIV viral load correlates with the risk of transmission of HIV. In men with acute HIV infection, the viral load in semen appears to follow a similar pattern to that seen in blood, with the highest levels occurring at approximately 20 days after infection or six days after the onset of symptoms for those with an acute retroviral syndrome [36]. (See "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Viral transmission'.)

One model of heterosexual infection suggested that in the absence of other sexually transmitted diseases, men could be expected to infect 7 to 24 percent of susceptible female partners during the first two months of HIV infection [36]. However, another study suggested that accurate estimates of transmission rates at the population level have been limited by imprecise definitions of acute HIV infection [37].

SUMMARY AND RECOMMENDATIONS

●HIV has several targets, including dendritic cells, macrophages, and CD4+ T cells. (See 'Target cells' above.)

●HIV RNA levels rapidly increase from the earliest quantifiable measure to a peak level that usually coincides with seroconversion. (See 'Viremia' above.)

●At the time of initial infection, patients have a large number of susceptible CD4+ T cells and no HIV-specific immune responses. Viral replication is therefore rapid and plasma viremia is extraordinarily high. However, when virus-specific CD8+ cytotoxic T lymphocytes emerge, plasma viremia levels fall precipitously. (See 'Cellular immune response' above.)

●Symptomatic acute HIV infection has been reported in all major risk categories including men who have sex with men (MSM), people who inject drugs, and health care workers with a needle-stick exposure. (See 'Epidemiology' above.)

●Patients with early HIV infection are highly contagious to others, given the typical high viral loads that are seen transiently in early HIV infection. (See 'Infectivity' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.