HIV (human immunodeficiency virus) is a retrovirus that infects immune cells, progressively weakening the body’s ability to fight infections and certain cancers. Left untreated, it advances through distinct stages over years, ultimately reaching the condition known as AIDS. Modern antiretroviral therapy can halt that progression and reduce the virus to undetectable levels in the blood, but the infection cannot yet be fully eliminated. Understanding the causes, stages, and treatment options matters not just for people living with HIV but for anyone who wants to separate outdated fears from current science.
How HIV Gets Inside Your Cells
HIV targets a specific type of white blood cell called the CD4+ T cell, which normally coordinates the immune response. The virus carries a surface protein called Env that latches onto the CD4 receptor on the cell’s surface and then binds a second molecule, known as a coreceptor, to complete its entry. That two-step docking triggers the viral and cell membranes to fuse, letting the virus’s genetic material slip inside.1PubMed Central. HIV: cell binding and entry The two main coreceptors are CCR5 and CXCR4. Early in infection, the virus tends to use CCR5, while strains that appear later in untreated disease often shift to using CXCR4.2PubMed. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes This coreceptor switch is clinically meaningful because it tracks with a broadening of the virus’s target cell range and, in many cases, faster disease progression.
Once inside, HIV does something unusual for a virus: it converts its RNA genome into DNA using an enzyme called reverse transcriptase, then stitches that DNA copy into the host cell’s own chromosomes with a second enzyme called integrase.3PubMed Central. Interaction between Reverse Transcriptase and Integrase Is Required for Reverse Transcription during HIV-1 Replication From that point on, every time the cell divides, the viral DNA is copied along with it. This integration step is what makes HIV so difficult to eradicate and why treatment must be lifelong.
How HIV Spreads Between People
HIV is transmitted through specific body fluids: blood, semen, rectal and vaginal secretions, and breast milk. The main routes are sexual contact, sharing needles or syringes, mother-to-child transmission during pregnancy, birth, or breastfeeding, and, historically, contaminated blood products.4PubMed Central. HIV transmission Casual contact, saliva, sweat, and tears do not carry enough virus to transmit infection.
Not all exposures carry equal risk. A systematic review of per-act transmission probabilities found that blood transfusion with infected blood carries the highest risk, followed by mother-to-child exposure, then sexual exposures, and finally other needle-related exposures. Among sexual routes, receptive anal intercourse carried the highest estimated risk at about 138 infections per 10,000 exposures, while oral sex carried the lowest. The combined use of condoms and antiretroviral treatment of the HIV-positive partner reduced sexual transmission risk by roughly 99%.5PubMed Central. Estimating per-act HIV transmission risk: a systematic review That last figure underpins much of modern prevention strategy.
For reasons researchers still do not fully understand, the strains that use the CCR5 coreceptor are preferentially transmitted across all routes, even when the person transmitting the virus carries a mixture of CCR5-using and CXCR4-using strains.4PubMed Central. HIV transmission This transmission bottleneck has implications for vaccine design and for understanding why certain genetic mutations affecting CCR5 offer protection.
The Origins of the Virus
HIV did not appear out of nowhere. Both HIV-1 (responsible for the global pandemic) and HIV-2 (largely confined to West and Central Africa) originated from simian immunodeficiency viruses that naturally infect African primates.6PubMed Central. Origins of HIV and the AIDS pandemic HIV-2 is generally less aggressive and progresses more slowly than HIV-1.7PubMed Central. The Confluence of HIV-1 and HIV-2: Implications for Disease Progression and Insights for Therapy
Most cross-species jumps produced viruses that spread only in a limited way among humans. The exception was one particular transmission event involving a chimpanzee virus in southeastern Cameroon, which gave rise to HIV-1 group M, the lineage behind the vast majority of infections worldwide.6PubMed Central. Origins of HIV and the AIDS pandemic Phylogenetic analyses have shown that at least four independent cross-species transmissions produced distinct HIV-1 lineages, and one or two of those may have passed through gorillas before reaching humans.8PubMed Central. The evolution of HIV-1 and the origin of AIDS
The Three Stages of HIV Disease
Without treatment, HIV disease typically moves through three stages over a span of years. The pace varies widely between individuals, but the general trajectory follows a recognizable pattern shaped by what the virus does to CD4+ T cells.
Acute Infection
Within the first few weeks after exposure, HIV replicates explosively. Many people experience flu-like symptoms: fever, sore throat, swollen lymph nodes, rash, and muscle aches. These symptoms resolve on their own, which is partly why acute HIV infection often goes unrecognized. Beneath the surface, the damage is severe. The gut-associated lymphoid tissue is an important early target, and primary infection causes dramatic depletion of CD4+ T cells in the intestinal lining.9PubMed Central. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy The gut harbors a large proportion of the body’s immune cells, and this early assault compromises the mucosal immune barrier in ways that persist long after initial symptoms disappear.10PubMed. Pathogenesis of HIV in the gastrointestinal tract
Viral load in the blood peaks during acute infection, making this the most infectious period. The immune system eventually mounts a partial response that drives viral levels down to a lower “set point,” but it never clears the virus entirely.
Chronic Infection
After the acute phase, most people enter a prolonged period where they feel relatively well. This stage can last a decade or more without treatment. The virus continues replicating at lower levels, however, and the immune system stays in a state of chronic activation as it tries to keep up. That persistent immune activation is now considered the driving force behind the gradual loss of CD4+ T cells and the eventual progression to AIDS.11PubMed Central. HIV-associated chronic immune activation Even in people who achieve viral suppression on treatment, a residual level of chronic immune activation persists, and the extent of that residual activation is associated with CD4 cell loss.11PubMed Central. HIV-associated chronic immune activation
AIDS
AIDS is defined by a CD4 count falling below 200 cells per cubic millimeter of blood, or by the appearance of specific opportunistic infections or cancers. At that threshold, the immune system can no longer defend against pathogens it would normally control. Infections that become common at this stage include Pneumocystis pneumonia, toxoplasmosis, Mycobacterium avium complex, and progressive multifocal leukoencephalopathy.12PubMed Central. Diagnosing HIV-related disease: using the CD4 count as a guide Without treatment, survival after an AIDS diagnosis is typically measured in months to a few years. With treatment started at this stage, immune recovery is still possible, though it tends to be slower and less complete than when therapy begins earlier.
The Hidden Reservoir That Blocks a Cure
Antiretroviral therapy can suppress HIV to the point where standard blood tests cannot detect it. Yet the infection persists. The reason is latency: HIV integrates its DNA into long-lived memory CD4+ T cells that are essentially resting. In these cells, the viral genes sit silent, invisible to both the immune system and antiviral drugs. This latent reservoir is considered the main barrier to a cure.13Immunity. Mechanisms of HIV-1 Persistence and Strategies for Eradication
The reservoir forms early. When activated CD4+ T cells are infected and then transition into a resting memory state, the conditions are right for the viral DNA to go quiet: certain host factors that would normally drive viral gene expression get tucked away.13Immunity. Mechanisms of HIV-1 Persistence and Strategies for Eradication Making the problem worse, infected cells that have gone latent can divide and produce clones of themselves without waking the virus, expanding the reservoir over time.14PubMed Central. Different human resting memory CD4+ T cell subsets show similar low inducibility of latent HIV-1 proviruses Because memory T cells can survive for decades, stopping treatment at any point allows the virus to rebound from this hidden stockpile, usually within weeks.
Treatment With Antiretroviral Therapy
Modern HIV treatment uses combinations of drugs that target different steps in the viral life cycle. The standard approach, called combination antiretroviral therapy, typically involves two or three drugs from at least two different classes. Drug classes include those that block reverse transcriptase, those that block integrase, and those that block the virus’s protease enzyme. Integrase inhibitors have become a cornerstone of first-line regimens because of their potency and tolerability.15PubMed Central. Retroviral integrase: Structure, mechanism, and inhibition
When taken consistently, these drug combinations reduce the viral load to undetectable levels in most people. The CD4 count typically recovers, the risk of opportunistic infections drops, and life expectancy approaches that of the general population. Therapy is not curative, though, and long-term use brings its own challenges, including the potential for drug side effects and the emergence of drug resistance if the virus is not fully suppressed.16PubMed Central. Clinical management of HIV drug resistance Managing resistance requires specialized testing to identify which mutations the virus has acquired, guiding the selection of alternative drug combinations.17PubMed Central. Management of Virologic Failure and HIV Drug Resistance
Prevention Beyond Condoms
The finding that effective treatment reduces sexual transmission by roughly 99% gave rise to the concept known as U=U: undetectable equals untransmittable. When a person living with HIV maintains an undetectable viral load through consistent treatment, they do not transmit the virus to sexual partners. Awareness of U=U varies globally, but a 25-country study found that people who had discussed U=U with their healthcare provider had better treatment adherence, higher rates of viral suppression, and were more likely to disclose their HIV status.18BMJ Journals. Undetectable equals untransmittable (U = U): awareness and associations with health outcomes among people living with HIV in 25 countries
For people who are HIV-negative but at higher risk of exposure, pre-exposure prophylaxis (PrEP) offers another layer of protection. Daily oral PrEP with tenofovir and emtricitabine is highly effective when taken consistently, though real-world effectiveness in earlier clinical trials fell short of expectations, largely because of adherence challenges.19PubMed Central. Current and Future PrEP Medications and Modalities: On-demand, Injectables, and Topicals Long-acting injectable PrEP with cabotegravir, given every eight weeks, addresses the adherence problem and modeling studies have projected it could prevent more infections than oral PrEP at the same coverage levels.20The Lancet HIV. Effectiveness of long-acting injectable pre-exposure prophylaxis with cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in men who have sex with men: a modelling study Other approaches under investigation include topical microbicide gels and vaginal rings, though these have underperformed in trials, again largely due to inconsistent use.19PubMed Central. Current and Future PrEP Medications and Modalities: On-demand, Injectables, and Topicals
Preventing Mother-to-Child Transmission
Without intervention, HIV can pass from mother to child during pregnancy, labor, delivery, or breastfeeding. Antiretroviral drugs given to the mother during pregnancy and labor, and to the infant after birth, substantially reduce this risk. A Cochrane review found that zidovudine regimens cut the risk of mother-to-child transmission by roughly half compared to placebo, and also reduced infant death in the first year and maternal death.21Cochrane Database of Systematic Reviews. Interventions for preventing mother‐to‐child transmission of HIV infection Longer courses of treatment proved more effective than shorter ones, and multidrug regimens further improved outcomes.22PubMed Central. HIV: prevention of mother-to-child transmission
Elective cesarean delivery before the onset of labor also reduces transmission risk. One trial found a large reduction compared to vaginal delivery.23Cochrane Database of Systematic Reviews. Interventions for reducing the risk of mother‐to‐child transmission of HIV infection In high-resource settings where mothers can access full antiretroviral therapy throughout pregnancy and achieve viral suppression, the risk of transmission drops to under 1%. The challenges are greater in settings where drugs and monitoring are less available, and where breastfeeding, which carries its own transmission risk, may be the only safe feeding option for infants.
What HIV Does to the Brain
HIV enters the central nervous system within days of initial infection. The virus crosses the blood-brain barrier by hitching rides inside infected immune cells or, in some cases, by passing through as free viral particles when the barrier’s integrity is compromised. Once inside the brain, it infects resident immune cells such as microglia and macrophages, as well as certain support cells called astrocytes.24Trends in Molecular Medicine. Unraveling the changing pathophysiology of HIV-associated neurocognitive impairment These cells are long-lived and resistant to the virus’s cell-killing effects, meaning they can harbor HIV for years, even in people whose blood viral load is undetectable. Brain autopsy studies have confirmed replication-capable virus in these cells despite sustained viral suppression, and the viral proteins they produce can damage surrounding neurons.24Trends in Molecular Medicine. Unraveling the changing pathophysiology of HIV-associated neurocognitive impairment
The practical result is that some people living with treated HIV experience neurocognitive difficulties: trouble with concentration, memory, or processing speed. The severe dementia that characterized the pre-treatment era is now rare, but milder forms of cognitive impairment remain common enough to be a focus of ongoing research. The brain essentially serves as a separate viral compartment that antiretroviral drugs penetrate unevenly, complicating efforts to fully control the infection throughout the body.
Aging With HIV and Chronic Inflammation
As antiretroviral therapy has transformed HIV from a fatal illness into a manageable chronic condition, a new set of challenges has emerged. People living with HIV who maintain viral suppression can now expect to live for decades, but they tend to develop age-related diseases earlier than their HIV-negative peers. Conditions like cardiovascular disease, metabolic syndrome, bone loss, neurocognitive decline, and certain non-HIV-related cancers appear at younger ages in this population.25PubMed Central. Ageing and inflammation in patients with HIV infection
The underlying driver appears to be chronic inflammation. Even with viral suppression, markers of inflammation and immune activation remain elevated in people with HIV. Elevated levels of inflammatory markers such as C-reactive protein, D-dimer, and interleukin-6 have been linked to increased risk of cardiovascular events and overall mortality in this group.26PubMed Central. Aging, inflammation, and HIV infection Researchers describe this as a form of accelerated aging, drawing parallels to “inflammaging,” the low-grade chronic inflammation seen in elderly individuals without HIV.25PubMed Central. Ageing and inflammation in patients with HIV infection This means that managing HIV today involves far more than just keeping the virus suppressed; it requires attention to cardiovascular risk, bone density, metabolic health, and mental health in ways that mirror geriatric care for much older patients.
Why a Small Number of People Resist HIV Naturally
A tiny fraction of people exposed to HIV never become infected, or become infected but control the virus to extremely low levels without medication. These individuals, sometimes called elite controllers, have given researchers valuable clues about immune protection. Strong host immune responses play a role, as do specific genetic factors.27PubMed. Elite controllers and lessons learned for HIV-1 cure
The best-known genetic factor is a mutation called CCR5-delta32. Because HIV typically uses the CCR5 coreceptor to enter cells, people who carry two copies of this deletion (one from each parent) produce a truncated CCR5 protein that the virus cannot use. A meta-analysis found that individuals homozygous for the delta32 deletion had a significantly reduced risk of acquiring HIV-1, while those carrying just one copy had a modestly increased susceptibility compared to people without the mutation.28PubMed Central. The CCR5-Delta32 Genetic Polymorphism and HIV-1 Infection Susceptibility: a Meta-analysis Among people who were exposed but remained uninfected, carrying the delta32 allele was associated with a significantly lower risk of infection.28PubMed Central. The CCR5-Delta32 Genetic Polymorphism and HIV-1 Infection Susceptibility: a Meta-analysis Other genetic variations that reduce CCR5 expression on cell surfaces have been identified in HIV controllers as well.29PubMed Central. Reduced CCR5 expression among Uganda HIV controllers
The delta32 mutation is most common in people of Northern European descent and rare in African and Asian populations, which means it plays a limited role in the global epidemic. But it has had an outsized impact on cure research.
Where Cure Research Stands
The only people considered cured of HIV to date received stem cell transplants from donors who carried two copies of the CCR5-delta32 mutation. The transplant replaced their immune system with one the virus could not easily infect. Five such transplants using CCR5-delta32 donor cells have been documented.30Frontiers in Genome Editing. In pursuit of an HIV cure: from stem cell transplants to gene therapies These cases proved that a cure is biologically possible, but stem cell transplantation is far too risky and resource-intensive to be a scalable strategy. It is reserved for people who need the transplant for another reason, such as blood cancer.
Current research is pursuing several less drastic approaches. Gene therapy aims to edit a person’s own cells to disable CCR5 or to cut the integrated viral DNA out of infected cells.30Frontiers in Genome Editing. In pursuit of an HIV cure: from stem cell transplants to gene therapies The “shock and kill” strategy tries to wake latent virus from its hiding places so the immune system or drugs can destroy the newly activated cells. An alternative, “block and lock,” takes the opposite approach: permanently silencing the latent viral DNA so it can never reactivate.31PubMed Central. HIV Cure: How Far We Have Come? Cell-based immunotherapies, including engineered T cells and broadly neutralizing antibodies, are also under investigation.32PubMed Central. Advancing towards HIV-1 remission: Insights and innovations in stem cell therapies None of these has yet proven reliably curative in clinical trials, but the field has moved from asking whether a cure is possible to asking which strategy can be made safe and scalable enough to deploy widely.
Testing and the Window Period
HIV testing has evolved considerably. Older tests detected only antibodies, which the body takes weeks to produce after infection, creating a “window period” during which a recently infected person could test negative. Modern fourth-generation tests detect both antibodies and a viral protein called p24 antigen simultaneously, narrowing that window. The current recommended diagnostic approach uses a fourth-generation test as the initial screen, followed by a test that can differentiate between HIV-1 and HIV-2 if the screen is positive, with nucleic acid testing available as a tiebreaker when results are ambiguous.33PubMed Central. Performance of a Fourth-Generation HIV Screening Assay and an Alternative HIV Diagnostic Testing Algorithm
Rapid tests and self-test kits have expanded access to screening, but they typically detect only antibodies and have a longer window period than laboratory-based fourth-generation assays. For anyone who has had a recent high-risk exposure, a negative rapid test within the first few weeks does not rule out infection, and follow-up testing is warranted. Early diagnosis matters enormously: starting treatment during acute infection preserves more CD4+ T cells, limits the size of the latent reservoir, and prevents onward transmission during the period of peak infectiousness.